PMID: 28649742 (Patient)   Terms: meta-analysis
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0		Genotranscriptomic meta-analysis of the CHD family chromatin remodelers in human cancers : initial evidence of an oncogenic role for CHD7 .
1		Chromodomain helicase DNA binding proteins ( CHD ) are characterized by N-terminal tandem chromodomains and a central ATP -dependent helicase domain .
2		CHDs govern the cellular machinery's access to DNA , thereby playing critical roles in various cellular processes including transcription , proliferation , and DNA damage repair .
3		Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer .
4		However , we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer .
5		We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10,000 primary cancer specimens from 32 tumor types , focusing on breast cancers .
6	Μ	We identified associations among recurrent copy number alteration , gene expression , clinicopathological features , and patient survival .
7	Μ	We found that CHD7 was the most commonly gained/amplified and mutated , whereas CHD3 was the most deleted across the majority of tumor types , including breast cancer .
8		Overexpression of CHD7 was more prevalent in aggressive subtypes of breast cancer and was significantly correlated with high tumor grade and poor prognosis .
9		CHD7 is required to maintain open , accessible chromatin , thus providing fine-tuning of transcriptional regulation of certain classes of genes .
10	Μ	We found that CHD7 expression was positively correlated with a small subset of classical oncogenes , notably NRAS , in breast cancer .
11		Knockdown of CHD7 inhibits cell proliferation and decreases gene expression of several CHD7 targets , including NRAS , in breast cancer cell lines .
12		Thus , our results demonstrate the oncogenic potential of CHD7 and its association with poor prognostic parameters in human cancer .

PMID: 28521409 (Patient)   Terms:
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0		Evaluation of a novel approach to circulating tumor cell isolation for cancer gene panel analysis in patients with breast cancer .
1		Liquid biopsy isolation of circulating tumor cells ( CTCs ) allows the genomic analysis of CTCs , which is useful in the determination of personalized cancer therapy .
2		In the present study , CTCs from patients with breast cancer were enriched and successfully analyzed using cancer gene panel analysis .
3		Blood samples from 11 patients with breast cancer were collected and CTCs enriched for using size-based filtration .
4		The enriched CTCs were analyzed using immunofluorescence staining with antibodies directed against epithelial cell adhesion molecule ( EpCAM ) and cluster of differentiation 45 .
5	Μ	The genomic DNA of CTCs was extracted , amplified and 50 genes screened for mutations using the Ion AmpliSeq Cancer Hotspot Panel v2 .
6		EpCAM staining detected CTCs in 10/11 patients and the average CTC count was 3.9 in 5 ml blood .
7		The average purity of enriched CTCs was 14.2+/-29.4% and the average amount of amplified DNA was 28.6+/-11.9 microg .
8	Μ	Catalogue Of Somatic Mutations In Cancer mutations were detected in the CTCs and included IDH2 , TP53 , NRAS , IDH1 , PDGFRA , HRAS , STK11 , EGFR , PTEN , MLH1 , PIK3CA , CDKN2A , KIT and SMARCB1 .
9		In conclusion , a novel size-based filtration approach for the isolation of CTCs was evaluated and successfully applied for the genomic analysis of CTCs from patients with breast cancer .

PMID: 28229982 (Patient)   Terms:
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0	✓	Circulating-free DNA Mutation Associated with Response of Targeted Therapy in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer .	GM-ASS-RO
1		BACKGROUND :
2		The addition of anti-human epidermal growth factor receptor 2 ( HER2 )- targeted drugs , such as trastuzumab , lapatinib , and trastuzumab emtansine ( T-DM1 ) , to chemotherapy significantly improved prognosis of HER2-positive breast cancer patients .
3		However , it was confused that metastatic patients vary in the response of targeted drug .
4		Therefore , methods of accurately predicting drug response were really needed .
5		To overcome the spatial and temporal limitations of biopsies , we aimed to develop a more sensitive and less invasive method of detecting mutations associated with anti-HER2 therapeutic response through circulating-free DNA ( cfDNA ) .
6		METHODS :
7		From March 6 , 2014 to December 10 , 2014 , 24 plasma samples from 20 patients with HER2-positive metastatic breast cancer who received systemic therapy were eligible .
8	Μ	We used a panel for detection of hot-spot mutations from 50 oncogenes and tumor suppressor genes , and then used targeted next-generation sequencing ( NGS ) to identify somatic mutation of these samples in those 50 genes .
9		Samples taken before their first trastuzumab administration and subsequently proven with clinical benefit were grouped into sensitive group .
10		The others were collected after disease progression of the trastuzumab-based therapy and were grouped into the resistant group .
11		RESULTS :
12	Μ	A total of 486 single - nucleotide variants from 46 genes were detected .
13		Of these 46 genes , LONGTOKEN , proto-oncogene c-Kit ( KIT ) , and tumor protein p53 ( TP53 ) were the most common mutated genes .
14		Seven genes , including epidermal growth factor receptor ( EGFR ) , G protein subunit alpha S ( GNAS ) , HRas proto-oncogene ( HRAS ) , mutL homolog 1 ( MLH1 ) , cadherin 1 ( CDH1 ) , neuroblastoma RAS viral oncogene homolog ( NRAS ) , and NOTCH1 , that only occurred m utations in the resistant group were associated with the resistance of targeted therapy .
15	Μ	In addition , we detected a HER2 S855I mutation in two patients who had persistent benefits from anti-HER2 therapy .
16		CONCLUSION :
17		Targeted NGS of cfDNA has potential clinical utility to detect biomarkers from HER2-targeted therapies .

PMID: 28082821 (Patient)   Terms: , mice, mice breast cancer models
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0		Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein .
1		Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics .
2		It is developing quickly in the field of cancer therapy .
3		For example , KRAS , NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer ( CRC ) .
4		Besides for these well-known mutations , the purpose of performing larger genetic testing in this pathology is unknown .
5		Recent reports have shown that using the poly ADP ribose polymerase ( PARP ) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast , ovarian and prostate cancers .
6		We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses .
7	Μ	The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients ( Check2 for the first patient and RAD51C for the second one ) .
8		Both patients were treated with off-label usage of olaparib .
9	Μ	While the first patient showed clinical benefit , reduction of carcinoembryonic antigen tumor marker and radiologic response , the second patient quickly presented a progression of the tumor .
10	Μ	Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed .
11	✓	Interestingly , deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models .
12		Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency .

PMID: 27899992 (Patient)   Terms: , rat
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0		Beside P53 and PTEN : Identification of molecular alterations of the RAS/MAPK and PI3K/AKT signaling pathways in high-grade serous ovarian carcinomas to determine potential novel therapeutic targets .
1		Despite great histological and molecular heterogeneity , the clinical management of high-grade ovarian carcinomas remains unspecialized .
2		As a major subgroup , high-grade serous ovarian carcinomas ( HGSOCs ) require novel therapies .
3		In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations , the molecular diagnostic method of next generation sequencing ( NGS ) was performed to identify 'druggable' targets that could provide access to innovative therapy .
4		The present study was performed in 45 HGSOC patients ( mean age , 591 years ; range , 25-87 years ) with histologically proven HGSOC .
5	Μ	Breast cancer 1/2 ( BRCA1/2 ) germline mutations were screened in 17 patients with a familial or personal history of cancer , which was justified by oncogenetic investigations .
6		Tumor protein 53 ( P53 ) and phosphatase and tensin homolog ( PTEN ) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry .
7		Somatic mutations of Kirsten rat sarcoma viral oncogene homolog , neuroblastoma RAS viral oncogene homolog ( NRAS ) , B-Raf proto - oncogene , serine/threonine kinase , LONGTOKEN and MET proto-oncogene , receptor tyrosine kinase ( MET ) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis .
8		With a median follow-up of 38 months ( range , 6-93 months ) , 20 patients are alive , 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy .
9		P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients .
10	Μ	The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival .
11	Μ	In total , 2 NRAS ( exon 3 ) , 3 PIK3CA ( exon 5 and 10 ) and 5 MET mutations ( exons 14 and 18 ) were detected .
12	Μ	In HGSOCs , in addition to P53 and PTEN alterations , somatic genetic abnormalities can be detected using NGS and provide molecular rationale for targeted therapies , potentially offering novel therapeutic opportunities to patients .

PMID: 27863474 (Cell)   Terms:
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0		Hypoxic resistance of KRAS mutant tumor cells to 3-Bromopyruvate is counteracted by Prima-1 and reversed by N-acetylcysteine .
1		BACKGROUND :
2		The metabolic inhibitor 3-bromopyruvate ( 3-BrPA ) is a promising anti-cancer alkylating agent , shown to inhibit growth of some colorectal carcinoma with KRAS mutation .
3		Recently , we demonstrated increased resistance to 3-BrPA in wt p53 tumor cells compared to those with p53 silencing or mutation .
4		Since hypoxic microenvironments select for tumor cells with diminished therapeutic response , we investigated whether hypoxia unequally increases resistance to 3-BrPA in wt p53 MelJuso melanoma harbouring ( Q61L ) -mutant NRAS and wt BRAF , C8161 melanoma with ( G12D ) -mutant KRAS (G464E) -mutant BRAF , and A549 lung carcinoma with a KRAS (G12S)- mutation .
5		Since hypoxia increases the toxicity of the p53 activator , Prima-1 against breast cancer cells irrespective of their p53 status , we also investigated whether Prima-1 reversed hypoxic resistance to 3-BrPA .
6		RESULTS :
7		In contrast to the high susceptibility of hypoxic mutant NRAS MelJuso cells to 3-BrPA or Prima-1 , KRAS mutant C8161 and A549 cells revealed hypoxic resistance to 3-BrPA counteracted by Prima-1 .
8		In A549 cells , Prima-1 increased p21CDKN1mRNA , and reciprocally inhibited mRNA expression of the SLC2A1-GLUT1 glucose transporter-1 and ALDH1A1 , gene linked to detoxification and stem cell properties. 3-BrPA lowered CAIX and VEGF mRNA expression .
9		Death from joint Prima-1 and 3-BrPA treatment in KRAS mutant A549 and C8161 cells seemed mediated by potentiating oxidative stress , since it was antagonized by the anti-oxidant and glutathione precursor N-acetylcysteine .
10		CONCLUSIONS :
11		This report is the first to show that Prima-1 kills hypoxic wt p53 KRAS-mutant cells resistant to 3-BrPA , partly by decreasing GLUT-1 expression and exacerbating pro-oxidant stress .

PMID: 27758885 (Cell)   Terms:
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0		Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation .
1		Alternative polyadenylation ( APA ) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3' untranslated region ( 3' UTR ) sequences .
2		To identify posttranscriptional-regulatory events affected by APA in breast tumors , tumor datasets were analyzed for recurrent APA events .
3		Motif mapping of the changed 3' UTR regions found that APA -mediated removal of Pumilio regulatory elements ( PRE ) was unusually common .
4	Μ	Breast tumor subtype-specific APA profiling identified triple-negative breast tumors as having the highest levels of APA .
5		To determine the frequency of these events , an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA .
6	Μ	APA -mediated shortening of NRAS and c-JUN was seen frequently , and this correlated with changes in the expression of downstream targets .
7	Μ	mRNA stability and luciferase assays demonstrated APA -dependent alterations in RNA and protein levels of affected candidate genes .
8		Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative , but more invasive than non-APA tumors .
9		RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA .
10		Overexpression of CSTF3 was common in triple-negative breast cancer cell lines , and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN .
11		Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA , primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex .
12		Cancer Res ; 76 ( 24 ) ; 7231-41 .
13		(c) 2016 AACR .

PMID: 27628192 (Patient)   Terms: clinical trial, retrospective
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0		Clinical implications of routine genomic mutation sequencing in PIK3CA/AKT1 and KRAS/NRAS/BRAF in metastatic breast cancer .
1		BACKGROUND :
2		There is increasing interest in the molecular profiling of tumour tissues in order to investigate alternative breast cancer ( BC ) therapies .
3	Μ	However , the impact of genomic screening for druggable mutations with targeted gene panel sequencing ( TGPS ) in routine practice remains controversial .
4		METHODS :
5	Μ	This is a retrospective analysis of data from a genomic screening programme at our institution , in which we performed simplified TGPS for mutations in PIK3CA , AKT1 , KRAS , NRAS , and BRAF in order to select patients for targeted therapy clinical trials .
6		The genomes of archived samples of primary ( PT ) and/or metastatic ( MT ) tumours from advanced BC patients were analysed with MassARRAY technology ( Sequenom MassARRAY , OncoCarta v10 ) .
7		The level of PTEN expression was assessed by immunohistochemistry .
8		The primary endpoint was to identify the proportion of BC patients with PI3 K and MAPK alterations who were included in clinical trials using targeted therapies against these pathways .
9		RESULTS :
10		Two hundred and fifteen metastatic BC patients ( 65 PT and 168 MT ) were included .
11	Μ	Fifty-two patients ( 2419 % ) were enrolled in tailored clinical trials , of whom 29 ( 5577 , 1349 % of all patients screened ) harboured mutations targeted by the study drug .
12	Μ	Moreover , 12 wild-type patients out of the 215 ( 558 % ) were included in the clinical trials for which mutation analysis was an inclusion criteria .
13		All the patients received drugs targeting the PI3K-AKT pathway and only two were given combinations directed against the PI3K and MAPK pathways .
14		PI3KCA mutations were present in 33.7 % ( 61/181 ) of the patients , 45.83 % in PTs and 29.32 % in MTs .
15	Μ	AKT1 mutations were detected in 5.48 % ( 8/146 ) of patients and PTEN loss in 34.67 % ( 52/150 ) .
16		KRAS , NRAS , and BRAF mutations were present in 12.06 , 5.67 , and 3.18 % of patients , respectively .
17		CONCLUSIONS :
18	Μ	Genomic screening with a simplified TGPS is feasible , and was used to identify 13.49 % of patients who were included in clinical trials using targeted therapy against the mutations they harboured ; PI3KCA mutations were the most frequent aberration in our series .

PMID: 27602167 (Cell)   Terms:
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0		Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation .
1		Hyperactive Ras promotes proliferation and malignant phenotypic conversion of cells in cancer .
2		Ras protein must be associated with cellular membranes for its oncogenic activities through post-translational modifications , including farnesylation .
3		Farnesyltransferase ( FTase ) is essential for H-Ras membrane targeting , and H-Ras , but not N-Ras , has been demonstrated to cause an invasive phenotype in MCF10A breast epithelial cells .
4		In the present study , it was observed that an FTase inhibitor ( FTI ) , FTI-277 , blocked epidermal growth factor ( EGF )- induced H-Ras activation , but not N-Ras activation in MDA-MB-231 cells , which express wild-type H-Ras and N-Ras .
5		FTI-277 exerted a more potent inhibitory effect on the proliferation of H-Ras-MCF10A cells and Hs578T breast cancer cells expressing an active mutant of H-Ras than that of MDA-MB-231 cells .
6		The invasive/migratory phenotypes of the H-Ras-MCF10A and Hs578T cells were effectively inhibited by FTI-277 treatment .
7		By contrast , FTI-277 did not affect the invasive/migratory phenotypes of MDA-MB-231 cells .
8		However , the EGF -induced invasion of MDA-MB-231 cells was decreased by FTI-277 , implicating that FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation .
9		Taken together , the results of the present study suggest that FTase inhibition by FTI-277 may be an effective strategy for targeting H-Ras-mediated proliferation , migration and invasion of breast cells .

PMID: 27488531 (None)   Terms: In Vivo, in vivo, xenograft, clinical trial
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0		An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor -Based Therapies in Melanoma .
1		Aberrant cell -cycle progression is a hallmark feature of cancer cells .
2		Cyclin-dependent kinases 4 and 6 ( CDK4/6 ) drive progression through the G1 stage/NN of the cell cycle , atleast in part , by inactivating the tumor suppressor , retinoblastoma .
3		CDK4/6 are targetable and the selective CDK4/6 inhibitor , palbociclib , was recently FDA approved for the treatment of estrogen receptor -positive , HER2-negative advanced breast cancer .
4		In cutaneous melanoma , driver mutations in NRAS and BRAF promote CDK4/6 activation , suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved .
5		However , the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined .
6		Furthermore , in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking .
7		Here , we describe the heterogeneous effects of CDK4/6 inhibitors , the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors , and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts .
8		These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma .
9		Cancer Res ; 76 ( 18 ) ; 5455-66 .
10		(c) 2016 AACR .

PMID: 27437940 (Cell)   Terms:
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0		ASPP2 Is a Novel Pan-Ras Nanocluster Scaffold .
1		Ras-induced senescence mediated through ASPP2 represents a barrier to tumour formation .
2		It is initiated by ASPP2 's interaction with Ras at the plasma membrane , which stimulates the Raf/MEK/ERK signaling cascade .
3		Ras to Raf signalling requires Ras to be organized in nanoscale signalling complexes , called nanocluster .
4		We therefore wanted to investigate whether ASPP2 affects Ras nanoclustering .
5		Here we show that ASPP2 increases the nanoscale clustering of all oncogenic Ras isoforms , H-ras , K-ras and N-ras .
6		Structure -function analysis with ASPP2 truncation mutants suggests that the nanocluster scaffolding activity of ASPP2 converges on its alpha-helical domain .
7		While ASPP2 increased effector recruitment and stimulated ERK and AKT phosphorylation , it did not increase colony formation of RasG12V transformed NIH/3T3 cells .
8		By contrast , ASPP2 was able to suppress the transformation enhancing ability of the nanocluster scaffold Gal-1 , by competing with the specific effect of Gal-1 on H-rasG12V - and K-rasG12V-nanoclustering , thus imposing ASPP2's ERK and AKT signalling signature .
9		Similarly , ASPP2 robustly induced senescence and strongly abrogated mammosphere formation irrespective of whether it was expressed alone or together with Gal-1 , which by itself showed the opposite effect in Ras wt or H-ras mutant breast cancer cells .
10		Our results suggest that Gal-1 and ASPP2 functionally compete in nanocluster for active Ras on the plasma membrane .
11		ASPP2 dominates the biological outcome , thus switching from a Gal-1 supported growth-promoting setting to a senescence inducing and stemness suppressive program in cancer cells .
12		Our results support Ras nanocluster as major integrators of tumour fate decision events .

PMID: 27410677 (None)   Terms:
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0		A Small Molecule That Represses Translation of G-Quadruplex-Containing mRNA .
1		The G-quadruplexes form highly stable nucleic acid structures , which are implicated in various biological processes in both DNA and RNA .
2		Although DNA G-quadruplexes have been studied in great detail , biological roles of RNA G-quadruplexes have received less attention .
3		Here , a screening of a chemical library permitted identification of a small-molecule tool that binds selectively to RNA G-quadruplex structures .
4		The polyaromatic molecule , RGB-1 , stabilizes RNA G-quadruplex , but not DNA versions or other RNA structures .
5		RGB-1 intensified the G-quadruplex-mediated inhibition of RNA translation in mammalian cells , decreased expression of the NRAS proto-oncogene in breast cancer cells , and permitted identification of a novel sequence that forms G-quadruplex in NRAS mRNA .
6		RGB-1 may serve as a unique tool for understanding cellular roles of RNA G-quadruplex structures .

PMID: 27236916 (Patient)   Terms:
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0		Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis .
1		Papillary thyroid carcinoma ( PTC ) has a wide geographic variation in incidence ; it is most common in Saudi Arabia , where it is only second to breast cancer as the most common cancer among females .
2		Genomic profiling of PTC from Saudi Arabia has not been attempted previously .
3	Μ	We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations , then sequenced these genes by using a next-generation gene -panel approach in an additional 785 samples .
4	Μ	In addition to BRAF , N-RAS , and H-RAS , which have previously been shown to be recurrently mutated in PTC , our analysis highlights additional genes , including thyroglobulin ( TG ) , which harbored somatic mutations in 3% of the entire cohort .
5	✓	Surprisingly , although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway , their presence was associated with a significantly worse clinical outcome , which suggests a pathogenic role beyond driving initial oncogenesis .	GM-ASS-RO
6	Μ	Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations ( p <0001 ) , including events of apparent clonal expansion .
7		Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution .

PMID: 27220763 (Patient)   Terms:
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0		Prognostic factors in the myoepithelial-like spindle cell type of metaplastic breast cancer .
1		Metaplastic breast carcinoma ( MBC ) comprises a heterogeneous group of tumors with difficult to predict biological behavior .
2		A subset of MBC , characterized by spindle-shaped tumor cells with a myoepithelial-like immunophenotype , was entered into a retrospective study ( n = 42 , median follow-up time 43 months ) .
3		Molecular parameters ( DNA sequences of mutation hot spots in AKT1 , ALK , APC , BRAF , CDH1 , CTNNB1 , EGFR , ERBB2 , FBXW7 , FGFR2 , FOXL2 , GNAQ , GNAS , KIT , KRAS , MAP2K1 , MET , MSH6 , NRAS , PDGFRA , PIK3CA , PTEN , SF3B1 , SMAD4 , SRC , SRSF2 , STK11 , TP53 , and U2AF1 ; copy numbers for EGFR , c-myc , FGFR , PLAG , c-met ) were assessed .
4		None of the patients had axillary lymph node involvement .
5		In 13 cases , local recurrence developed after surgery ( 309 % ) .
6		Distant metastasis occurred in seven patients ( 17 % ; four after local recurrence ) .
7		The most frequent genetic alteration was PIK3CA mutation ( 50 % of cases ) .
8		None of the pathological parameters ( size , grade , stage , Ki-67 labeling index ) was significantly associated with disease-free survival ( DFS ) or overall survival ( OS ) .
9		PIK3CA mutation , especially the H1047R type , tended to adversely affect OS .
10		Type of resection ( mastectomy vs. breast-conserving therapy , width of margins ) or adjuvant radiotherapy had no influence on DFS or OS , whereas in the group treated with radio-/chemotherapy , no local recurrence or metastasis and no death occurred .
11		We conclude that the spindle cell type of MBC with myoepithelial features exhibits a higher frequency of PIK3CA mutation than other types of metaplastic or basal-like breast cancer and may benefit from combined radio-/chemotherapy .
12		Classical pathological parameters are not helpful in identifying the high-risk tumors among this subgroup of MBC .

PMID: 26899600 (None)   Terms:
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0		MEGSA : A Powerful and Flexible Framework for Analyzing Mutual Exclusivity of Tumor Mutations .
1		The central challenges in tumor sequencing studies is to identify driver genes and pathways , investigate their functional relationships , and nominate drug targets .
2	Μ	The efficiency of these analyses , particularly for infrequently mutated genes , is compromised when subjects carry different combinations of driver mutations .
3		Mutual exclusivity analysis helps address these challenges .
4		To identify mutually exclusive gene sets ( MEGS ) , we developed a powerful and flexible analytic framework based on a likelihood ratio test and a model selection procedure .
5		Extensive simulations demonstrated that our method outperformed existing methods for both statistical power and the capability of identifying the exact MEGS , particularly for highly imbalanced MEGS .
6		Our method can be used for de novo discovery , for pathway-guided searches , or for expanding established small MEGS .
7		We applied our method to the whole-exome sequencing data for 13 cancer types from The Cancer Genome Atlas ( TCGA ) .
8		We identified multiple previously unreported non-pairwise MEGS in multiple cancer types .
9	✓	For acute myeloid leukemia , we identified a MEGS with five genes ( FLT3 , IDH2 , NRAS , KIT , and TP53 ) and a MEGS ( NPM1 , TP53 , and RUNX1 ) whose mutation status was strongly associated with survival ( p = 6.7 x 10 ( -4 ) ) .	GM-ASS-RO
10	Μ	For breast cancer , we identified a significant MEGS consisting of TP53 and four infrequently mutated genes ( ARID1A , AKT1 , MED23 , and TBL1XR1 ) , providing support for their role as cancer drivers .

PMID: 26882547 (None)   Terms: in vivo, xenograft, mouse
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0		miR-515-5p controls cancer cell migration through MARK4 regulation .
1		Here , we show that miR-515-5p inhibits cancer cell migration and metastasis .
2		RNA-seq analyses of both oestrogen receptor receptor -positive and receptor -negative breast cancer cells overexpressing miR-515-5p reveal down-regulation of NRAS , FZD4 , CDC42BPA , PIK3C2B and MARK4 mRNAs .
3		We demonstrate that miR-515-5p inhibits MARK4 directly 3' UTR interaction and that MARK4 knock-down mimics the effect of miR-515-5p on breast and lung cancer cell migration .
4		MARK4 overexpression rescues the inhibitory effects of miR-515-5p , suggesting miR-515-5p mediates this process through MARK4 down-regulation .
5		Furthermore , miR-515-5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer .
6		Conversely , miR-515-5p overexpression prevents tumour cell dissemination in a mouse metastatic model .
7	✓	Moreover , high miR-515-5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival , respectively .	GE-ASS-RO
8		Taken together , these data demonstrate the importance of miR-515-5p/MARK4 regulation in cell migration and metastasis across two common cancers .

PMID: 26575426 (None)   Terms: This review
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0		Germline gene polymorphisms predisposing domestic mammals to carcinogenesis .
1		Cancer is a complex disease caused in part by predisposing germline gene polymorphisms .
2		Knowledge of carcinogenesis in companion mammals ( dog and cat ) and some livestock species ( pig and horse ) is quite advanced .
3		The prevalence of certain cancers varies by breed in these species , suggesting the presence of predisposing genetic variants in susceptible breeds .
4		This review summarizes the present understanding of germline gene polymorphisms , including BRCA1 , BRCA2 , MC1R , KIT , NRAS and RAD51 , associated with predisposition to melanoma , mammary cancer , osteosarcoma and histiocytic sarcoma in dogs , cats , pigs and horses .
5		The predisposing variants in these species are discussed in the context of human germline gene polymorphisms associated with the same types of cancer .

PMID: 26413934 (Cell)   Terms: in vivo, in vitro, xenograft, mouse tumor models, mouse
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0		A novel role for flotillin-1 in H-Ras-regulated breast cancer aggressiveness .
1		Elevated expression and aberrant activation of Ras have been implicated in breast cancer aggressiveness .
2		H-Ras , but not N-Ras , induces breast cell invasion .
3		A crucial link between lipid rafts and H-Ras function has been suggested .
4		This study sought to identify the lipid raft proteins responsible for H-Ras-induced tumorigenicity and invasiveness of breast cancer .
5		We conducted a comparative proteomic analysis of lipid raft proteins from invasive MCF10A human breast epithelial cells engineered to express active H-Ras and non-invasive cells expressing active N-Ras .
6		Here , we identified a lipid raft protein flotillin-1 as an important regulator of H-Ras activation and breast cell invasion .
7		Flotillin-1 was required for epidermal growth factor -induced activation of H-Ras , but not that of N-Ras , in MDA-MB-231 triple-negative breast cancer ( TNBC ) cells .
8		Flotillin-1 knockdown inhibited the invasiveness of MDA-MB-231 and Hs578T TNBC cells in vitro and in vivo .
9		In xenograft mouse tumor models of these TNBC cell lines , we showed that flotillin-1 played a critical role in tumor growth .
10		Using human breast cancer samples , we provided clinical evidence for the metastatic potential of flotillin-1 .
11		Membrane staining of flotillin-1 was positively correlated with metastatic spread ( p = 0013 ) and inversely correlated with patient disease-free survival rates ( p = 0005 ) .
12		Expression of flotillin-1 was associated with H-Ras in breast cancer , especially in TNBC ( p <0001 ) .
13		Our findings provide insight into the molecular basis of Ras isoform-specific interplay with flotillin-1 , leading to tumorigenicity and aggressiveness of breast cancer .

PMID: 26244871 (None)   Terms:
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0		CCL18 -mediated down-regulation of miR98 and miR27b promotes breast cancer metastasis .
1		Our previous work has indicated that CCL18 secreted by tumor-associated macrophages ( TAMs ) promotes breast cancer metastasis , which is associated with poor patient prognosis .
2		However , it remains unclear whether microRNAs ( miRNAs ) , which may modulate multiple cellular pathways , are involved in the regulation of CCL18 signaling and the ensuing metastasis of breast cancer .
3	Μ	In this study , we demonstrated that CCL18 reduces miR98 and miR27b expression via the N-Ras/ERK/PI3K/NFkappaB/Lin28b signaling pathway , while down-regulation of these mRNAs feedbacks to increase N-Ras and Lin28b levels .
4		This cascade of events forms a positive feedback loop that sustains the activation of CCL18 signaling .
5		More importantly , reduction in miR98 and miR27b enhances the epithelial-mesenchymal transition ( EMT ) of breast cancer cells , and thus promotes breast cancer metastasis .
6		These findings suggest that down-regulation of miR98 and miR27b promotes CCL18 -mediated invasion and migration of breast cancer cells .

PMID: 26166574 (None)   Terms:
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0		Wild-Type N-Ras , Overexpressed in Basal-like Breast Cancer , Promotes Tumor Formation by Inducing IL-8 Secretion via JAK2 Activation .
1		Basal-like breast cancers ( BLBCs ) are aggressive , and their drivers are unclear .
2		We have found that wild-type N-RAS is overexpressed in BLBCs but not in other breast cancer subtypes .
3		Repressing N-RAS inhibits transformation and tumor growth , whereas overexpression enhances these processes even in preinvasive BLBC cells .
4		We identified N-Ras-responsive genes , most of which encode chemokines ; e.g. , IL8 .
5	✓	Expression levels of these chemokines and N-RAS in tumors correlate with outcome .	GE-ASS-RO
6		N-Ras , but not K-Ras , induces IL-8 by binding and activating the cytoplasmic pool of JAK2 ; IL-8 then acts on both the cancer cells and stromal fibroblasts .
7	✓	Thus , BLBC progression is promoted by increasing activities of wild-type N-Ras , which mediates autocrine/paracrine signaling that can influence both cancer and stroma cells .	GM-REG-RO

PMID: 25750332 (None)   Terms:
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0		Primary malignant melanoma of the breast : case report and review of the literature .
1		BACKGROUND :
2		Melanoma of the breast is a rare disease and may present as a metastatic manifestation of primary cutaneous melanoma or as primary malignant melanoma of the breast ( PMMB ) .
3		Clinical presentations of PMMB vary and surgery is the mainstay of treatment .
4		CASE REPORT :
5		We present the case of a 54-year-old woman with a primary malignant melanoma of the left breast .
6		She was treated with mastectomy , axillary sentinel lymph node excision and primary reconstruction with a tissue expander .
7		Final histology revealed a malignant melanoma with 10 cm in the largest diameter .
8		Molecular characterization by DNA-sequencing showed B-RAF , N-RAS and c-kit wild types .
9	Μ	Immunohistochemical characterization demonstrated weak expression of S100 and melan-A and strong expression of polyclonal S100 .
10		HMB45 , tyrosine kinase and the cytokeratins AE1/AE3 and MNF 116 were not expressed .
11		Lymphoma-specific markers ( CD30 , CD3 , CD20 ) and sarcoma-specific markers ( desmin , actin , CD34 ) were also negative .
12		The tumor proliferation rate according to Mib1-staining was 90% .
13		Staging of the abdomen , chest , head and bones showed no evidence of metastases .
14		A dermatological examination showed no primary melanoma of the skin .
15		Interferon -alpha was suggested as adjuvant therapy but declined by the patient .
16		With a follow-up of 6 months , the patient is still alive with no evidence of disease .
17		CONCLUSION :
18		PMMB is rare and may be successfully treated with surgical excision .
19		Locally advanced PMMB may occur without regional and distant metastases .

PMID: 25685069 (Cell)   Terms:
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0		The association between expressions of Ras and CD68 in the angiogenesis of breast cancers .
1		OBJECTIVE :
2		Angiogenesis is a critical step of breast cancer metastasis .
3		Oncogenic Ras promotes the remodeling of cancer microenviroment .
4		Tumor-associated macrophages ( TAMs ) are a prominent inflammatory cell population emerging in the microenviroment and facilitating the angiogenesis and metastasis .
5		In the present study , we tried to investigate the relationship between the expression of Ras and infiltration of TAM , both of which could further promote angiogenesis .
6		METHODS :
7		Expressions of Ras , CD68 and CD34 were assessed by immunohistochemistry .
8		The infiltration of macrophages was evaluated by counting the number of CD68(+) cells .
9		Vessel endothelial cells were defined as CD34(+) cells .
10		Angiogenesis vascularity was defined by microvessel density ( MVD ) assay through counting the number of vessels per field counted in the area of highest vascular density .
11		The Kaplan-Meier survival analysis was used to estimate the overall survival ( OS ) .
12		Macrophages were derived from monocytes in the presence of macrophage colony-stimulating-factor ( MCSF ) .
13		Breast cancer cells were treated with macrophage-conditioned medium ( MCM ) and tested the expressions of K - , H - and N-Ras by using realtime-PCR .
14		RESULTS :
15		Ras positive status was correlated with ER , PR and Her-2 positivity , larger tumour size and lymph node metastasis , as well as higher TNM stages .
16		A higher number of CD68(+) cells was correlated with larger tumour size , higher TNM stages and Her-2 positivity .
17		Both Ras positivity and infiltration of CD68(+) macrophages correlated with poor OS .
18		The number of CD68(+) cells was positively correlated with the expression of Ras .
19		Treatment with MCM did not up-regulate but repressed the expression of Ras .
20		Both up-regulation of Ras and infiltration of TAMs correlated with increased MVD .
21		CONCLUSION :
22		Expression of Ras and infiltration of TAM were positively correlated , and both participated in angiogenesis .
23		Elevated Ras could be responsible for the infiltration of TAM .

PMID: 25364765 (None)   Terms:
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0		Cardio-miRNAs and onco-miRNAs : circulating miRNA-based diagnostics for non-cancerous and cancerous diseases .
1		Cardiovascular diseases and cancers are the leading causes of morbidity and mortality in the world .
2		MicroRNAs ( miRNAs ) are short non-coding RNAs that primarily repress target mRNAs .
3		Here , miR-24 , miR-125b , miR-195 , and miR-214 were selected as representative cardio-miRs that are upregulated in human heart failure .
4		To bridge the gap between miRNA studies in cardiology and oncology , the targets and functions of these miRNAs in cardiovascular diseases and cancers will be reviewed .
5		ACVR1B , BCL2 , BIM , eNOS , FGFR3 , JPH2 , MEN1 , MYC , p16 , and ST7L are miR-24 targets that have been experimentally validated in human cells .
6		ARID3B , BAK1 , BCL2 , BMPR1B , ERBB2 , FGFR2 , IL6R , MUC1 , SITR7 , Smoothened , STAT3 , TET2 , and TP53 are representative miR-125b targets .
7		ACVR2A , BCL2 , CCND1 , E2F3 , GLUT3 , MYB , RAF1 , VEGF , WEE1 , and WNT7A are representative miR-195 targets .
8		BCL2L2 , ss-catenin , BIM , CADM1 , EZH2 , FGFR1 , NRAS , PTEN , TP53 , and TWIST1 are representative miR-214 targets .
9		miR-125b is a good cardio-miR that protects cardiomyocytes ; miR-195 is a bad cardio-miR that elicits cardiomyopathy and heart failure ; miR-24 and miR-214 are bi-functional cardio-miRs .
10		By contrast , miR-24 , miR-125b , miR-195 , and miR-214 function as oncogenic or tumor suppressor miRNAs in a cancer ( sub ) type -dependent manner .
11		Circulating miR-24 is elevated in diabetes , breast cancer and lung cancer .
12		Circulating miR-195 is elevated in acute myocardial infarction , breast cancer , prostate cancer and colorectal adenoma .
13		Circulating miR-125b and miR-214 are elevated in some cancers .
14		Cardio-miRs and onco-miRs bear some similarities in functions and circulation profiles .
15		miRNAs regulate WNT , FGF , Hedgehog and other signaling cascades that are involved in orchestration of embryogenesis and homeostasis as well as pathogenesis of human diseases .
16		Because circulating miRNA profiles are modulated by genetic and environmental factors and are dysregulated by genetic and epigenetic alterations in somatic cells , circulating miRNA association studies ( CMASs ) within several thousands of cases each for common non-cancerous diseases and major cancers are necessary for miRNA-based diagnostics .

PMID: 25350317 (Cell)   Terms: In vivo
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0		Combining a BCL2 inhibitor with the retinoid derivative fenretinide targets melanoma cells including melanoma initiating cells .
1		Investigations from multiple laboratories support the existence of melanoma initiating cells ( MICs ) that potentially contribute to melanoma's drug resistance .
2		ABT-737 , a small molecule BCL-2/BCL-XL/BCL-W inhibitor , is promising in cancer treatments , but not very effective against melanoma , with the antiapoptotic protein MCL-1 as the main contributor to resistance .
3		The synthetic retinoid fenretinide N- ( 4-hydroxyphenyl ) retinamide ( 4-HPR ) has shown promise for treating breast cancers .
4		Here , we tested whether the combination of ABT-737 with 4-HPR is effective in killing both the bulk of melanoma cells and MICs .
5	Μ	The combination synergistically decreased cell viability and caused cell death in multiple melanoma cells lines ( carrying either BRAF or NRAS mutations ) but not in normal melanocytes .
6		The combination increased the NOXA expression and caspase -dependent MCL-1 degradation .
7		Knocking down NOXA protected cells from combination-induced apoptosis , implicating the role of NOXA in the drug synergy .
8		The combination treatment also disrupted primary spheres ( a functional assay for MICs ) and decreased the percentage of aldehyde dehydrogenase ( high ) cells ( a marker of MICs ) in melanoma cell lines .
9		Moreover , the combination inhibited the self-renewal capacity of MICs , measured by secondary sphere-forming assays .
10		In vivo , the combination inhibited tumor growth .
11		Thus , this combination is a promising treatment strategy for melanoma , regardless of mutation status of BRAF or NRAS .

PMID: 25107706 (None)   Terms:
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0		Change or die : targeting adaptive signaling to kinase inhibition in cancer cells .
1		Small molecule kinase inhibitors have proven enormously successful at delivering impressive responses in patients with cancers as diverse as chronic myeloid-leukemia , melanoma , breast cancer and small cell lung cancer .
2		Despite this , resistance is commonplace and most patients ultimately fail therapy .
3		One emerging observation is the rapid rewiring of signaling that occurs across multiple cancer types when driver oncogene function is inhibited .
4		These adaptive signaling changes seem critical in delivering some of the earliest survival signals that allow small numbers of cells to evade therapy .
5		In this commentary we review the mechanisms that contribute to the robustness of signaling networks within cancer cells and suggest new therapeutic strategies to limit treatment failure .

PMID: 24662829 (Patient)   Terms:
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0		A mutant p53/let-7i-axis-regulated gene network drives cell migration , invasion and metastasis .
1		Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein .
2		Besides losing tumor suppressor activity , some hotspot p53 mutants gain oncogenic functions .
3		This effect is mediated in part , through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters .
4		Here , we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53 .
5		In breast cancer patients , significantly decreased let-7i levels were associated with missense mutations in p53 .
6		Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63 .
7		Introduction of let-7i to mutant p53 cells significantly inhibited migration , invasion and metastasis by repressing a network of oncogenes including E2F5 , LIN28B , MYC and NRAS .
8		Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration , invasion and metastasis .

PMID: 24400121 (Cell)   Terms: , mouse
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0		miR-223 is a coordinator of breast cancer progression as revealed by bioinformatics predictions .
1		MicroRNAs are single-stranded non-coding RNAs that simultaneously down-modulate the expression of multiple genes post-transcriptionally by binding to the 3'UTRs of target mRNAs .
2		Here we used computational methods to predict microRNAs relevant in breast cancer progression .
3	Μ	Specifically , we applied different microRNA target prediction algorithms to various groups of differentially expressed protein -coding genes obtained from four breast cancer datasets .
4		Six potential candidates were identified , among them miR-223 , previously described to be highly expressed in the tumor microenvironment and known to be actively transferred into breast cancer cells .
5		To investigate the function of miR-223 in tumorigenesis and to define its molecular mechanism , we overexpressed miR-223 in breast cancer cells in a transient or stable manner .
6		Alternatively we overexpressed miR-223 in mouse embryonic fibroblasts or HEK293 cells and used their conditioned medium to treat tumor cells .
7		With both approaches , we obtained elevated levels of miR-223 in tumor cells and observed decreased migration , increased cell death in anoikis conditions and augmented sensitivity to chemotherapy but no effect on adhesion and proliferation .
8	Μ	The analysis of miR-223 predicted targets revealed enrichment in cell death and survival-related genes and in pathways frequently altered in breast cancer .
9		Among these genes , we showed that protein levels for STAT5A , ITGA3 and NRAS were modulated by miR-223 .
10		In addition , we proved that STAT5A is a direct miR-223 target and highlighted a possible correlation between miR-223 and STAT5A in migration and chemotherapy response .
11	Μ	Our investigation revealed that a computational analysis of cancer gene expression datasets can be a relevant tool to identify microRNAs involved in cancer progression and that miR-223 has a prominent role in breast malignancy that could potentially be exploited therapeutically .

PMID: 24318467 (Patient)   Terms:
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0		Mutations in EGFR , BRAF and RAS are rare in triple-negative and basal-like breast cancers from Caucasian women .
1		Basal-like and triple-negative breast cancers usually display a high level of genomic instability and often carry TP53 mutations .
2		Mutations in EGFR have been reported in about 10 % triple-negative tumours from Chinese women , and there is some evidence that triple-negative and basal-like tumours might carry additional mutations against which targeted therapies are available .
3		We , therefore , sought to determine the frequency of 238 targetable mutations in 19 oncogenes ( including EGFR ) in a panel of basal-like and triple-negative breast cancers from Caucasian women .
4	Μ	We used the OncoCarta panel to screen for 238 mutations across 19 common oncogenes in 107 basal-like and triple-negative breast cancers from Caucasian women .
5		Mutations were then verified using Sanger sequencing or primer extension by iPLEX .
6	Μ	We identified and validated 10 mutations across five genes .
7	Μ	Most of the mutations were observed in the PIK3CA gene ( 18/107 , 168 % ) , while mutations in KRAS , NRAS , MET and AKT1 were present in only one tumour each ( 1/107 , 09 % ) .
8		Among the missense substitutions in PIK3CA the point mutation resulting in the amino acid change H1047R was the most frequent ( 8/18 , 44 % ) .
9	Μ	All mutations were mutually exclusive , apart from one basal-like breast tumour which harboured mutations in both MET (pT992I) and PIK3CA (pH1047R) .
10	Μ	We did not identify any mutations in the EGFR gene .
11	Μ	In conclusion , we found that with the exception of mutations in PIK3CA , these actionable oncogenic mutations on the Oncocarta panel are rare in basal-like and triple-negative breast cancers from Caucasian women .
12	Μ	Custom panels , designed to detect mutations identified by exome sequencing of basal-like and triple-negative breast cancers , are , therefore , needed to identify women who might be eligible for targeted treatment .

PMID: 24019232 (Cell)   Terms: in vitro
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0		Identification of annexin II as a novel secretory biomarker for breast cancer .
1		Early prediction of metastatic breast cancer is important for improvement of prognosis and survival rate .
2		The present study aimed to identify secreted protein biomarkers for detection of invasive breast cancer .
3		To this end , we performed a comparative proteomic analysis by a combination of 2DE and MALDI-TOF MS analysis of conditioned media from invasive H-Ras MCF10A human breast epithelial cells and noninvasive MCF10A and N-Ras MCF10A cells .
4		We identified a list of 25 proteins that were strongly detected in media of H-Ras MCF10A and focused on annexin II , which was shown to be involved in cell motility .
5		Invasive triple-negative human breast carcinoma cells , Hs578T , and MDA-MB-231 , showed increased levels of annexin II in media , demonstrating that secretion of annexin II correlated well with the invasive phenotype of cells .
6		We demonstrated a crucial role of annexin II in breast cell invasion/migration and actin cytoskeleton reorganization required for filopodia formation .
7		Annexin II levels in the plasma samples and breast cancer tissues of breast cancer patients were significantly higher than those of normal groups , providing a clinical relevance to our in vitro findings .
8		Taken together , we identified annexin II as a novel secretory biomarker candidate for invasive breast cancer , especially estrogen receptor -negative breast cancer .

PMID: 23904845 (None)   Terms:
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0		Primary dermal melanoma in a patient with a history of multiple malignancies : a case report with molecular characterization .
1		INTRODUCTION :
2		Primary dermal melanoma ( PDM ) is a recently described clinical entity accounting for less than 1% of all melanomas .
3		Histologically , it is located in the dermis or subcutaneous tissue , and it shows no connections with the overlying epidermis .
4		The differential diagnosis is principally made along with that of metastatic cutaneous melanoma .
5		CASE REPORT :
6		A 72-year-old Caucasian woman with a history of multiple cancers ( metachronous bilateral breast cancer , meningioma , clear cell renal cell carcinoma , uterine fibromatosis and intestinal adenomatous polyposis ) , came to our attention with a nodular lesion on her back .
7		After removal of the lesion , the histology report indicated malignant PDM or metastatic malignant melanoma .
8		The clinical and instrumental evaluation of the patient did not reveal any other primary tumour , suggesting the primitive nature of the lesion .
9		The absence of an epithelial component argued for a histological diagnosis of PDM .
10		Subsequently , the patient underwent a wide surgical excision with sentinel node biopsy , which was positive for metastatic melanoma .
11		Finally , the mutational status was studied in the main genes that regulate proliferation , apoptosis and cellular senescence .
12		No pathogenetic mutations in CDKN2A , BRAF , NRAS , KRAS , cKIT , TP53 and PTEN genes were observed .
13		This suggests that alternative pathways and low-frequency alterations may be involved .
14		CONCLUSIONS :
15		The differential diagnosis between PDM and isolated metastatic melanoma depends on the negativity of imaging studies and clinical findings for other primary lesions .
16		This distinction is important because 5-year survival rates in such cases are higher than in metastatic cases ( 80-100 vs. 5-20% , respectively ) .

PMID: 23895135 (None)   Terms:
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0		Phenotype of bone metastases of non-small cell lung cancer : epidermal growth factor receptor expression and K-RAS mutational status .
1		BACKGROUND :
2		Phyllodes tumors are uncommon breast tumors that account for less than 0.5% of all breast malignancies .
3		After metastases develop , the prognosis is poor , with very few patients living more than 1 year .
4		The biology of this unusual cancer is not understood and , consequently , no potential targets for treatments are currently available .
5		There has been an exponential increase in the number of commercially available tumor profiling services .
6		Herein , we report a case of metastatic malignant phyllodes tumor for which a comprehensive molecular analysis was performed by using Clinical Laboratory Improvement Amendments ( CLIA )- certified labs , providing new insights into the potential opportunities for molecularly targeted therapies for this extremely rare disease .
7		METHODS :
8		Next-generation sequencing was performed by using the FoundationOne platform ( Foundation Medicine , Cambridge , MA ) .
9		Whole - genome array-based comparative genomic hybridization ( array CGH ) was performed by using the DNAarray ( CombiMatrix Diagnostics , Irvine , CA ) .
10		Immunohistochemical and morphoproteomics analysis were performed at Consultative proteomics(R) , The University of Texas , UT Health Medical School , Houston , TX ( Robert E Brown Lab ) ; Clarient Diagnostics , Aliso Viejo , CA ; and Caris Life Sciences Target one , Irving , TX , USA .
11		RESULTS :
12	Μ	Next-generation sequencing showed 3 aberrant genes : activating mutation Q61L on NRAS ; inactivating mutations Q504* and K740* on RB1 ; and TP53 loss .
13		Whole - genome LONGTOKEN , chr. 8 ( MYC gene ) , and chr. 9 ( CDKN2A gene ) Deletions of chr. 17 ( TP53 ) , chr. 10 ( GATA3 ) , chr. 11 ( FGF4 and CCND1 genes ) , and chr.22 ( PDGFbeta ) .
14	Μ	Immunohistochemical analysis for relevant markers showed a positive staining for transducing-like enhancer of split ( TLE ) 3 ; secreted protein acidic and rich in cysteine ( SPARC ) was expressed at 2-3+ in the cytoplasm of the tumors cells , whereas mammalian target of rapamycin ( mTOR ) was expressed up to 2+ in the nuclei of the tumor cells .
15		CONCLUSIONS :
16		We describe for the first time an NRAS mutation with concomitant activation of PI3K/Akt/mTOR in phyllodes tumor .
17		We also found markers for sensitivity to taxane-based therapies , especially albumin-bound paclitaxel .
18		Exploring the biology of rare malignancies by CLIA certified labs may be reasonable strategy for the development of targeted treatments .

PMID: 23443307 (None)   Terms: This review, clinical trial, Phase I trial
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0		Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors of the stomach : report of three cases .
1		The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer .
2		Molecular alterations in these pathways are implicated in tumorigenesis and resistance to anticancer therapies .
3		The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are known to interact with each other at several nodes , and mounting evidence suggests that dual blockade of both pathways may be required to achieve anticancer effects in certain contexts .
4		This may include tumor types with a high frequency of RAS/RAF/MEK/ERK pathway activation , or situations in which dual pathway strategies may be required to overcome resistance to current targeted therapies .
5		Several clinical studies are currently evaluating the combination of PI3K and MEK inhibitors in a variety of different cancers with certain types of molecular alterations .
6		This review will summarize existing knowledge of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways , the cross-talk between them , and the current generation of PI3K and MEK inhibitors that target them .
7		The preclinical rationale for dual pathway inhibition will be discussed within the context of the major tumor types currently being explored in ongoing clinical trials , namely malignant melanoma with BRAF or NRAS mutations , and colorectal , ovarian , pancreatic , and basal-like breast cancers .
8		The emerging clinical profile of PI3K and MEK inhibitor combinations , as reported in Phase I trials , will also be discussed .

PMID: 23233531 (None)   Terms:
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0		miR148b is a major coordinator of breast cancer progression in a relapse-associated microRNA signature by targeting ITGA5 , ROCK1 , PIK3CA , NRAS , and CSF1 .
1	Μ	We identified in-frame fusion transcripts of KIF5B ( the kinesin family 5B gene ) and the RET oncogene , which are present in 1-2% of lung adenocarcinomas ( LADCs ) from people from Japan and the United States , using whole-transcriptome sequencing .
2		The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR , KRAS , HER2 and ALK , and a RET tyrosine kinase inhibitor , vandetanib , suppresses the fusion-induced anchorage -independent growth activity of NIH3T3 cells .

PMID: 22592534 (Patient)   Terms:
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0		MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF .
1		MiR-145 is known as a tumor suppressor in numerous human cancers .
2		However , its role in tumor angiogenesis remains poorly defined .
3		In this study , we found that miR-145 was significantly downregulated in breast cancer tissues by using 106 cases of normal and cancer tissues as well as in breast cancer cells .
4		MiR-145 exhibited inhibitory role in tumor angiogenesis , cell growth and invasion and tumor growth through the post-transcriptional regulation of the novel targets N-RAS and VEGF-A .
5		In addition , we provide evidence that the expression levels of miR-145 correlate inversely with malignancy stages of breast tumors , although there is no association between miR-145 levels and hormone receptor levels in breast cancer .
6		Taken together , these results demonstrate that miR-145 plays important inhibitory role in breast cancer malignancy by targeting N-RAS and VEGF-A , which may be potential therapeutic and diagnostic targets .

PMID: 22473698 (Patient)   Terms:
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0		Molecular characterization of EGFR and EGFR-downstream pathways in triple negative breast carcinomas with basal like features .
1		AIMS :
2		Triple negative breast cancer with basal like features ( TN-BCBL ) do not benefit from hormonal and anti-HER2 therapies .
3		As a considerable fraction of TN-BCBLs shows EGFR deregulation , EGFR-targeted therapies have been proposed as an option .
4		The characterization of EGFR and EGFR-downstream members may therefore provide important predictive information .
5		METHODS AND RESULTS :
6	Μ	Based on morphological and immunophenotypic features , we identified 38 TN-BCBLs that were subsequently investigated for alterations in EGFR signaling pathways .
7		EGFR and PTEN protein levels were studied by immunohistochemistry , EGFR gene status by FISH , EGFR , H-Ras , K-Ras , N-Ras , BRAF and PIK3CA gene mutations by direct sequencing .
8		EGFR overexpression and loss of PTEN expression characterized the majority of TN-BCBLs ( 76% and 74% of patients , respectively ) .
9		EGFR gene copy number gain ( FISH+ ) was identified in 51% of analyzable patients .
10	Μ	PIK3CA gene mutations were detected in three cases ( 8% ) , whereas EGFR , H-Ras , K-Ras , N-Ras and BRAF genes showed no mutations .
11	Μ	Overall , out of 17 patients classified as FISH+ , 12 cases ( 70% ) showed a concomitant alteration in PI3K/PTEN pathway .
12		CONCLUSIONS :
13	✓	These results provide evidence that the efficacy of anti-EGFR drugs in TN-BCBL patients could be impaired by frequent alterations in the PI3K/PTEN axis , and suggest that TN-BCBLs could benefit from tailored treatments against this axis .	RO-REG-GM

PMID: 21731475 (None)   Terms:
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0		Luteolin Regulation of Estrogen Signaling and Cell Cycle Pathway Genes in MCF-7 Human Breast Cancer Cells .
1		Budgetary impact of treatment with adjuvant imatinib for 1 year following surgical resection of Kit-positive localized gastrointestinal stromal tumors .

PMID: 21524920 (None)   Terms:
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0		Bombesin receptor antagonists [corrected]. 1 . Analogues with deleted , inverted or substituted amino acid residues .
1		Ras expression has been suggested to be a marker for tumor aggressiveness of breast cancer .
2		We previously showed that H-Ras , but not N-Ras , induced invasive/migratory phenotypes in MCF10A human breast epithelial cells .
3		The present study aimed to determine the role of granulocyte colony-stimulating factor in H-Ras-induced malignant progression of human breast epithelial cells .
4		Here , we show that G-CSF plays a crucial role in H-Ras-induced MCF10A cell invasion and migration .
5		The siRNA -mediated knockdown of G-CSF significantly reduced H-Ras-induced matrix metalloproteinase ( MMP ) -2 expression , as well as invasion/migration , suggesting the functional significance of G-CSF in the invasive phenotype of human breast cells .
6		Importantly , the induction of G-CSF expression conferred the invasive/migratory phenotypes to MCF10A cells with up-regulation of MMP-2 and activation of Rac1 , MKK3/6 , p38 MAPK , Akt , and ERKs .
7		Knockdown of Rac1 by siRNA significantly inhibited MMP-2 upregulation and invasiveness of G-CSF MCF10A cells , demonstrating that G-CSF-induced MMP-2 upregulation and invasive phenotype is mediated by Rac1 .
8		Using human breast tissues and sera from breast cancer patients , we further demonstrate that the expression level of G-CSF is strongly correlated with pathologically-diagnosed breast cancer .
9		These data provide a molecular basis for the crucial role of G-CSF in promoting invasiveness of human breast epithelial cells .

PMID: 21403836 (None)   Terms:
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0		Identification of H-Ras-specific motif for the activation of invasive signaling program in human breast epithelial cells .
1		Increased expression and/or activation of H-Ras are often associated with tumor aggressiveness in breast cancer .
2	✓	Previously , we showed that H-Ras , but not N-Ras , induces MCF10A human breast epithelial cell invasion and migration , whereas both H-Ras and N-Ras induce cell proliferation and phenotypic transformation .	GE-REG-RO
3		In an attempt to determine the sequence requirement directing the divergent phenotype induced by H-Ras and N-Ras with a focus on the induction of human breast cell invasion , we investigated the structural and functional relationships between H-Ras and N-Ras using domain -swap and site -directed mutagenesis approaches .
4		Here , we report that the hypervariable region ( HVR ) , consisting of amino acids 166 to 189 in H-Ras , determines the invasive/migratory signaling program as shown by the exchange of invasive phenotype by swapping HVR sequences between H-Ras and N-Ras .
5		We also demonstrate that the H-Ras-specific additional palmitoylation site at Cys184 is not responsible for the signaling events that distinguish between H-Ras and N-Ras .
6		Importantly , this work identifies the C-terminal HVR , especially the flexible linker domain with two consecutive proline residues Pro173 and Pro174 , as a critical domain that contributes to activation of H-Ras and its invasive potential in human breast epithelial cells .
7		The present study sheds light on the structural basis for the Ras isoform-specific invasive program of breast epithelial cells , providing information for the development of agents that specifically target invasion-related H-Ras pathways in human cancer .

PMID: 21281602 (Cell)   Terms:
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0		Activation of H-Ras and Rac1 correlates with epidermal growth factor -induced invasion in Hs578T and MDA-MB-231 breast carcinoma cells .
1		There is considerable experimental evidence that hyperactive Ras proteins promote breast cancer growth and development including invasiveness , despite the low frequency of mutated forms of Ras in breast cancer .
2		We have previously shown that H-Ras , but not N-Ras , induces an invasive phenotype mediated by small GTPase Rac1 in MCF10A human breast epithelial cells .
3		Epidermal growth factor ( EGF ) plays an important role in aberrant growth and metastasis formation of many tumor types including breast cancer .
4		The present study aims to investigate the correlation between EGF -induced invasiveness and Ras activation in four widely used breast cancer cell lines .
5		Upon EGF stimulation , invasive abilities and H-Ras activation were significantly increased in Hs578T and MDA-MB-231 cell lines , but not in MDA-MB-453 and T47D cell lines .
6		Using small interfering RNA ( siRNA ) to target H-Ras , we showed a crucial role of H-Ras in the invasive phenotype induced by EGF in Hs578T and MDA-MB-231 cells .
7		Moreover , siRNA-knockdown of Rac1 significantly inhibited the EGF -induced invasiveness in these cells .
8		Taken together , this study characterized human breast cancer cell lines with regard to the relationship between H-Ras activation and the invasive phenotype induced by EGF .
9		Our data demonstrate that the activation of H-Ras and the downstream molecule Rac1 correlates with EGF -induced breast cancer cell invasion , providing important information on the regulation of malignant progression in mammary carcinoma cells .

PMID: 20604919 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer .
1		INTRODUCTION :
2		Metastases to the brain from breast cancer have a high mortality , and basal-like breast cancers have a propensity for brain metastases .
3		However , the mechanisms that allow cells to colonize the brain are unclear .
4		METHODS :
5		We used morphology , immunohistochemistry , gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases , 22 unmatched brain metastases of breast cancer , 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites , including the brain .
6		RESULTS :
7		Most brain metastases were triple negative and basal-like .
8		The brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors .
9		Brain metastases from breast and other primary sites , and metastases to multiple organs in the autopsied cases , also contained somatic mutations in EGFR , HRAS , KRAS , NRAS or PIK3CA .
10		This paralleled the frequent activation of AKT and MAPK pathways .
11		In particular , activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors .
12		CONCLUSIONS :
13		Deregulated HER family receptors , particularly HER3 , and their downstream pathways are implicated in colonization of brain metastasis .
14		The need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors , and may even be effective in the absence of HER2 amplification ( that is , in triple negative/basal cancers ) .
15		However , the presence of activating mutations in PIK3CA , HRAS , KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules .

PMID: 19898424 (Patient)   Terms:
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0		High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast .
1		Papillary lesions of the breast have an uncertain relationship to the histogenesis of breast carcinoma , and are thus diagnostically and managerially challenging .
2		Molecular genetic studies have provided evidence that ductal carcinoma in situ and even atypical ductal hyperplasia are precursors of invasive carcinoma .
3		However , papillary lesions have been seldom studied .
4	Μ	We screened papillary breast neoplasms for activating point mutations in PIK3CA , AKT1 , and RAS protein -family members , which are common in invasive ductal carcinomas .
5		DNA extracts were prepared from sections of 89 papillary lesions , including 61 benign papillomas ( 28 without significant hyperplasia ; 33 with moderate to florid hyperplasia ) , 11 papillomas with atypical ductal hyperplasia , 7 papillomas with carcinoma in situ , and 10 papillary carcinomas .
6	Μ	Extracts were screened for PIK3CA and AKT1 mutations using mass spectrometry ; cases that were negative were further screened for mutations in AKT2 , BRAF , CDK , EGFR , ERBB2 , KRAS , NRAS , and HRAS .
7		Mutations were confirmed by sequencing or HPLC assay .
8	Μ	A total of 55 of 89 papillary neoplasms harbored mutations ( 62% ) , predominantly in AKT1 ( E17K , 27 cases ) and PIK3CA ( exon 20 >exon 9 , 27 cases ) .
9		Papillomas had more mutations in AKT1 ( 54% ) than in PIK3CA ( 21% ) , whereas papillomas with hyperplasia had more PIK3CA ( 42% ) than AKT1 ( 15% ) mutations , as did papillomas with atypical ductal hyperplasia ( PIK3CA 45% , AKT1 27% , and NRAS 9% ) .
10		Among seven papillomas with carcinoma in situ , three had AKT1 mutations .
11	Μ	The 10 papillary carcinomas showed an overall lower frequency of mutations , including 1 with an AKT1 mutation ( in a tumor arising from a papilloma ) , 1 with an NRAS gene mutation (Q61H) , and 2 with PIK3CA mutations ( 1 overlapping with the NRAS Q61H ) .
12		These findings indicate that approximately two-thirds of papillomas are driven by mutations in the PI3CA/AKT pathway .
13		Some papillary carcinomas may arise from these lesions , but others may have different molecular origins .

PMID: 18922970 (None)   Terms:
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0		Global gene expression profiling unveils S100A8/A9 as candidate markers in H-ras-mediated human breast epithelial cell invasion .
1		C-kit expression in the salivary gland neoplasms adenoid cystic carcinoma , polymorphous low-grade adenocarcinoma , and monomorphic adenoma .

PMID: 18649354 (Patient)   Terms: , rat, Animal cancer models, rat mammary models, rat mammary tumor
Sent#	Symbols	Sentence	Mnemonics
0		Absence of Ras mutations in rat DMBA -induced mammary tumors .
1		Animal cancer models reduce genetic background heterogeneity and thus , may facilitate identification and analysis of specific genetic aberrations in tumor cells .
2		Rat and human mammary glands have high similarity in physiology and show comparable hormone responsiveness .
3		Thus , spontaneous and carcinogen ( e.g. , NMU and DMBA )- induced rat mammary models are valuable tools for genetic studies of breast cancer .
4	Μ	In NMU -induced rat mammary tumors , activating mutations in Hras codon 12 have frequently been reported and are supposed to contribute to the mammary carcinogenic process .
5		Involvement of Ras mutations in DMBA -induced tumors is less clear .
6		In the present study we investigated the mutation status of the three Ras genes , Hras , Kras , and Nras , in DMBA -induced rat mammary tumors .
7	Μ	We examined codons 12 , 13 , and 61 of all three genes for mutations in 71 tumors using direct sequencing method that in experimental conditions is sensitive enough to detect single nucleotide mutations even when present in only 25% of the test sample .
8	Μ	No activating Ras gene mutation was found .
9		Thus , in contrast to NMU -induced rat mammary tumor , tumorigenesis in DMBA -induced rat mammary tumors seems to be independent on activating mutations in the Ras genes .
10		Our finding suggests that the genetic pathways selected in mammary tumor development are influenced by and perhaps dependent on the identity of the inducing agent , again emphasizing the importance of tumor etiology on the genetic changes in the tumor cells .

PMID: 18413234 (Cell)   Terms:
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0		Galectin-3 regulates RasGRP4 -mediated activation of N-Ras and H-Ras .
1	Μ	Galectin-3 ( Gal-3 ) is a pleiotropic beta-galactoside-binding protein expressed at relatively high levels in human neoplasms .
2		Its carbohydrate recognition domain ( CRD ) contains a hydrophobic pocket that can accommodate the farnesyl moiety of K-Ras .
3		Binding of K-Ras to Gal-3 stabilizes K-Ras in its active ( GTP-bound ) state .
4		Gal-3 , which does not interact with N-Ras , was nevertheless shown to reduce N-Ras-GTP in BT-549 cells by an unknown mechanism that we explored here .
5	Μ	First , comparative analysis of various cancer cell lines ( glioblastomas , breast cancer cells and ovarian carcinomas ) showed a positive correlation between low N-Ras-GTP/high K-Ras-GTP phenotype and Gal-3 expression levels .
6		Next we found that epidermal growth factor -stimulated GTP loading of N-Ras , but not of K-Ras , is blocked in cells expressing high levels of Gal-3 .
7		Activation of Ras guanine nucleotide releasing proteins ( RasGRPs ) by phorbol 12-myristate 13-acetate ( PMA ) or downregulation of Gal-3 by Gal-3 shRNA increased the levels of N-Ras-GTP in Gal-3 expressing cells .
8		We further show that the N-terminal domain of Gal-3 interacts with and inhibits RasGRP4 -mediated GTP loading on N-Ras and H-Ras proteins .
9		Growth of BT-549 cells stably expressing the Gal-3 N-terminal domain was strongly attenuated .
10		Overall , these experiments demonstrate a new control mechanism of Ras activation in cancer cells whereby the Gal-3 N-terminal domain inhibits activation of N-Ras and H-Ras proteins .

PMID: 18300768 (None)   Terms: This review
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0		The MAPK pathway in melanoma .
1		PURPOSE OF REVIEW : As understanding of molecular and genetic processes in cancer evolves , so does appreciation of tumor heterogeneity .
2		Tumor profiling has expanded knowledge of relevant pathways , and their interplay .
3		Similar to the revolution in breast cancer with the discovery and successful therapeutic targeting of HER2/neu , the melanoma field is rapidly evolving .
4		The MAPK pathway is dysregulated in most melanomas .
5		Several therapeutic agents directed against this pathway are in development .
6		This review summarizes current understanding of the MAPK pathway in melanoma biology and therapeutic strategies .
7		RECENT FINDINGS : Recent data support the concept of distinct groups of molecular and genetic abnormalities in melanomas , related to type of sun exposure and body site .
8		MAPK abnormalities , specifically BRAF or NRAS mutations , are most prevalent .
9		The efficacy of sorafenib , a multitargeted kinase inhibitor , in melanoma is still under evaluation .
10		While ineffective as a single agent , efficacy in combination with chemotherapy or targeted agents is being assessed .
11		More specific inhibitors of BRAF , or other MAPK members , may prove more effective .
12		SUMMARY : Tumor profiling has led to exciting advances .
13		The MAPK pathway is one of several potentially targetable pathways in melanoma .
14		Ultimately , combinatorial therapeutics against relevant disrupted pathways in specific tumors likely will prove most successful .

PMID: 18089795 (None)   Terms: , mouse model, mouse
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0		BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia .
1		Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis .

PMID: 17927918 (None)   Terms:
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0		Type I collagen-induced pro-MMP-2 activation is differentially regulated by H-Ras and N-Ras in human breast epithelial cells .
1		Tumor cell invasion and metastasis are often associated with matrix metalloproteinases ( MMPs ) , among which MMP-2 and MMP-9 are of central importance .
2		We previously showed that H-Ras , but not N-Ras , induced invasion of MCF10A human breast epithelial cells in which the enhanced expression of MMP-2 was involved .
3		MMP-2 is produced as a latent pro-MMP-2 ( 72kDa ) to be activated resulting the 62kDa active MMP-2 .
4		The present study investigated if H-Ras and/or N-Ras induces pro-MMP-2 activation of MCF10A cells when cultured in two-dimensional gel of type I collagen .
5		Type I collagen induced activation of pro-MMP-2 only in H-Ras MCF10A cells but not in N-Ras MCF10A cells .
6		Induction of active MMP-2 by type I collagen was suppressed by blocking integrin alpha2 , indicating the involvement of integrin signaling in pro-MMP-2 activation .
7		Membrane-type ( MT ) 1-MMP and tissue inhibitor of metalloproteinase ( TIMP ) -2 were up-regulated by H-Ras but not by N-Ras in the type I collagen-coated gel , suggesting that H-Ras-specific up-regulation of MT1-MMP and TIMP-2 may lead to the activation of pro-MMP-2 .
8		Since acquisition of pro-MMP-2 activation can be associated with increased malignant progression , these results may help understanding the mechanisms for the cell surface matrix-degrading potential which will be crucial to the prognosis and therapy of breast cancer metastasis .

PMID: 17314276 (Cell)   Terms:
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0		Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines .
1		Constitutive activation of the phosphatidylinositol-3-OH kinase ( PI3K ) and RAS signaling pathways are important events in tumor formation .
2		This is illustrated by the frequent genetic alteration of several key players from these pathways in a wide variety of human cancers .
3		Here , we report a detailed sequence analysis of the PTEN , PIK3CA , KRAS , HRAS , NRAS , and BRAF genes in a collection of 40 human breast cancer cell lines .
4	Μ	We identified a surprisingly large proportion of cell lines with mutations in the PI3K or RAS pathways ( 54% and 25% , respectively ) , with mutants for each of the six genes .
5		The PIK3CA , KRAS , and BRAF mutation spectra of the breast cancer cell lines were similar to those of colorectal cancers .
6		Unlike in colorectal cancers , however , mutational activation of the PI3K pathway was mutually exclusive with mutational activation of the RAS pathway in all but 1 of 30 mutant breast cancer cell lines ( P = 0001 ) .
7		These results suggest that there is a fine distinction between the signaling activators and downstream effectors of the oncogenic PI3K and RAS pathways in breast epithelium and those in other tissues .

PMID: 17079470 (None)   Terms:
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0		Activating transcription factor 2 mediates matrix metalloproteinase-2 transcriptional activation induced by p38 in breast epithelial cells .
1		Mounting evidence suggests a role for matrix metalloproteinase ( MMP ) -2 in the malignant progression of breast cancer cells .
2		We showed previously that H-Ras , but not N-Ras , induced invasion of MCF10A human breast epithelial cells through Rac-MKK3/6-p38 pathway resulted in MMP-2 up-regulation .
3		Activation of p38 pathway by MKK6 caused a selective up-regulation of MMP-2 .
4		In this study , we aimed to elucidate the transcriptional regulation of MMP-2 by p38 pathway leading to the invasive phenotype of MCF10A cells .
5	Μ	By using 5' deletion mutant constructs of MMP-2 promoter , we showed that deletion of the region containing activator protein-1 ( AP-1 ) site caused the greatest reduction of MMP-2 promoter activity both in MKK6 - and H-Ras-activated MCF10A cells , suggesting that the AP-1 binding site is critical for the MMP-2 promoter activation .
6		DNA binding and transcriptional activities of AP-1 were increased by MKK6 or H-Ras as evidenced by electrophoretic mobility shift assay and luciferase assay using an AP-1-driven plasmid .
7		By doing immunoinhibition assay and chromatin immunoprecipitation assay , we revealed the activating transcription factor ( ATF ) 2 as a transcription factor for MMP-2 gene expression through binding to the functional AP-1 site .
8		Activation of ATF2 , which depended on p38 activity , was crucial for MMP-2 promoter activity as well as induction of invasive and migrative phenotypes in MCF10A cells .
9		This is the first report revealing ATF2 as an essential transcription factor linking MKK3/6-p38 signaling pathway to MMP-2 up-regulation , providing evidence for a direct role of ATF2 activation in malignant phenotypic changes of human breast epithelial cells .

PMID: 16319984 (Cell)   Terms:
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0		High-resolution mapping of molecular events associated with immortalization , transformation , and progression to breast cancer in the MCF10 model .
1		BACKGROUND :
2		A comprehensive and consistent picture of the genetic changes that underlie breast cancer initiation , development , and progression remains unresolved .
3		The MCF10 series of cell lines represents many steps in that progression .
4		We performed high resolution mapping of the MCF10 series of cell lines to identify specific gene targets to elucidate the molecular correlates of immortalization , development , and progression of breast cancer at the level of individual genes .
5		DESIGN :
6		We evaluated the initial untransformed outgrowths ( MCF-10MS and MCF-10A ) with six transformed cell lines with benign proliferations ( MCF-10AT1 , MCF-10AT1kcl2 ) , carcinoma in situ ( MCF-10CA1h cl13 ) , and invasive carcinoma ( MCF-10CA1h cl2 , MCF-10CA1a cl1 , MCF-10CA1d cl1 ) .
7		Losses and gains of loci at 112 unique human genome sites were interrogated using the multiplex ligation-dependent probe amplification assay ( MLPA ) .
8		RESULTS :
9		Cytogenetic alterations in the four benign progenitors that persisted in the CIS and invasive cell lines corresponded to gains and losses of genes by MLPA .
10		MCF-10MS had only normal gene copies .
11		The untransformed MCF-10A had cytogenetic gain of 5q13-qter with corresponding gains of the IL3 , IL4 and IL12B genes at 5q31-q33 ; gain of distal 19q12-qter was reflected in gains in KLK3 and BAX gene loci at 19q13-q13.4 .
12		The observed genic gain of cMYC at 8q24.12 was not indicated by cytogenetics .
13		The apparently balanced t ( 3 ; 9 ) component of the t ( 3 ; 9 ) ( p13 ; p22 ) t ( 3 ; 5 ) ( p26 ; q31 ) resulted in complete loss of the CDKN2A and CDKN2B genes at 9p21 .
14		Additional clonal cytogenetic changes in the DCIS cell line (MCF-10A1h cl13) involving chromosomes 1 , 3 and 10 persisted in the invasive progeny , with gain of corresponding genes at 1p13 ( BCAR2 , BCAR3 , NRAS , TGFB2 ) , at 3p12-13 ( IL12A ) , and 3q21-27 ( MME , PIK3CA , BCL6 ) .
15		CONCLUSIONS :
16		Our study adopted a comprehensive exploration of genetic changes using high resolution molecular probes applied to the MCF10 family of cell lines to identify individual genes in a continuum starting from normal breast epithelial cells and progressing through immortalization , transformation and invasive malignancy .
17		Homozygous loss of CDKN2A and CDKN2B genes and gain of MYC were initiating immortalization events .
18		Transformation and progression to malignancy event were marked by gains of IL13 , VEGF , HRAS , TRAF2 , and BCAS2 , IL12A , and MME , respectively .

PMID: 16314303 (Patient)   Terms: , mouse
Sent#	Symbols	Sentence	Mnemonics
0		Identification and characterization of high affinity antisense PNAs for the human unr ( upstream of N-ras ) mRNA which is uniquely overexpressed in MCF-7 breast cancer cells .
1		We have recently shown that an MCF-7 tumor can be imaged in a mouse by PET with 64Cu-labeled Peptide nucleic acids ( PNAs ) tethered to the permeation peptide Lys4 that recognize the uniquely overexpressed and very abundant upstream of N-ras or N-ras related gene (unr mRNA) expressed in these cells .
2	Μ	Herein we describe how the high affinity antisense PNAs to the unr mRNA were identified and characterized .
3		First , antisense binding sites on the unr mRNA were mapped by an reverse transcriptase random oligonucleotide library ( RT-ROL ) method that we have improved , and by a serial analysis of antisense binding sites ( SAABS ) method that we have developed which is similar to another recently described method .
4		The relative binding affinities of oligodeoxynucleotides ( ODNs ) complementary to the antisense binding sites were then qualitatively ranked by a new Dynabead-based dot blot assay .
5		Dissociation constants for a subset of the ODNs were determined by a new Dynabead-based solution assay and were found to be 300 pM for the best binders in 1 M salt .
6		PNAs corresponding to the ODNs with the highest affinities were synthesized with an N-terminal CysTyr and C - terminal Lys4 sequence .
7		Dissociation constants of these hybrid PNAs were determined by the Dynabead-based solution assay to be about 10 pM for the highest affinity binders .

PMID: 16103080 (Cell)   Terms:
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0		Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells .
1		Galectin-3 ( Gal-3 ) , a pleiotropic carbohydrate -binding protein , is a selective binding partner of activated K-Ras-GTP .
2		Because both proteins are antiapoptotic and associated with cancer progression , we questioned the possible functional role of Gal-3 in K-Ras activation .
3		We found that overexpression of Gal-3 in human breast cancer cells (BT-549/Gal-3) coincided with a significant increase in wild-type ( wt ) K-Ras-GTP coupled with loss in wt N-Ras-GTP , whereas the nononcogenic Gal-3 mutant proteins [Gal-3 ( S6E ) and Gal-3 (G182A)] failed to induce the Ras isoform switch .
4		Only wt Gal-3 protein coimmunoprecipitated and colocalized with oncogenic K-Ras , resulting in its activation with radical alterations in Ras signaling pathway , whereby the activation of AKT and Ral was suppressed and shifted to the activation of extracellular signal-regulated kinase ( ERK ) .
5		Specific inhibitors for Ras or mitogen -activated protein/ERK kinase ( farnesylthiosalicylic acid and UO126 , respectively ) inhibited Gal-3 -mediated apoptotic resistance and anchorage -independent growth functions .
6		In conclusion , this study shows that Gal-3 confers on BT-549 human breast carcinoma cells several oncogenic functions by binding to and activation of wt K-Ras , suggesting that some of the molecular functions of Gal-3 are , atleast in part , a result of K-Ras activation .

PMID: 16006564 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		The farnesyl transferase inhibitor ( FTI ) SCH66336 ( lonafarnib ) inhibits Rheb farnesylation and mTOR signaling . Role in FTI enhancement of taxane and tamoxifen anti-tumor activity .
1		CDKN2A germline mutation frequency estimates are commonly based on families with several melanoma cases .
2		When we started counseling in a research setting on gene susceptibility analysis in northern and central Italy , however , we mostly found small families with few cases .
3		Here we briefly characterize those kindred , estimate CDKN2A/CDK4 mutation test yields , and provide indications on the possibility of implementing formal DNA testing for melanoma-prone families in Italy .
4		In September 1995 we started genetic counseling in a research setting at our Medical Genetics Center .
5	Μ	Screening for CDKN2A/CDK4 mutations was performed on families with two melanoma patients , one of whom was younger than 50 years at onset , the other complying with one of the following : 1 ) being a first-degree relative , 2 ) having an additional relative with pancreatic cancer , or 3 ) having multiple primary melanomas .
6		Sixty-two of 67 ( 80% ) melanoma cases met our criteria .
7	Μ	Four previously described CDKN2A mutations ( G101W , R24P , V126D , and N71S ) were found in 21 of the 62 families ( 34% ) with a high prevalence of G101W ( 18/21 ) .
8		The percentage of families with two melanoma cases/family harboring a mutation was low ( 7% , 2/27 ) , but rose to 45% ( 9/20 ) if one of the melanoma patients carried multiple melanomas or if pancreatic cancer was present in that family .
9		In the 15 families with three melanoma cases the presence of a mutation was higher ( 67% , 10/15 ) and reached 100% in the 4 families with four or more melanoma cases .
10	Μ	Our results suggest that CDKN2A/CDK4 counseling-based mutational analysis may be reasonably efficient also for families with two melanoma cases , if one patient carries multiple melanomas or if pancreatic cancer is present in the family .

PMID: 16002995 (None)   Terms:
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0		Locus -specific multifluor FISH analysis allows physical characterization of complex chromosome abnormalities in neoplasia .
1		Microvessel density , cyclo-oxygenase 2 expression , K-ras mutation and p53 overexpression in colonic cancer .

PMID: 15677464 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		H-Ras-specific activation of Rac-MKK3/6-p38 pathway : its critical role in invasion and migration of breast epithelial cells .
1		Human tumors frequently exhibit constitutively activated Ras signaling , which contributes to the malignant phenotype .
2		Mounting evidence suggests unique roles of the Ras family members , H-Ras , N-Ras and K-Ras , in normal and pathological conditions .
3		In an effort to dissect distinct Ras isoform-specific functions in malignant phenotypic changes , we previously established H-Ras - and N-Ras-activated MCF10A human breast epithelial cell lines .
4		Using these , we showed that p38 kinase is a key signaling molecule differentially regulated between H-Ras and N-Ras , leading to H-Ras-specific induction of invasive and migrative phenotypes .
5		The present study is to further investigate H-Ras - and N-Ras-mediated signaling pathways and to unveil how these pathways are integrated for regulation of invasive/migrative phenotypic conversion of human breast epithelial cells .
6		Here we report that the Rac-MAPK kinase ( MKK ) 3/6-p38 pathway is a unique signaling pathway activated by H-Ras , leading to the invasive/migrative phenotype .
7		In contrast , Raf-MEK-ERK and phosphatidylinositol 3-kinase -Akt pathways , which are fundamental to proliferation and differentiation , are activated by both H-Ras and N-Ras .
8		A significant role for p38 in cell invasion is further supported by the observation that p38 activation by MKK6 transfection is sufficient to induce invasive and migrative phenotypes in MCF10A cells .
9		Activation of the MKK6-p38 pathway results in a marked induction of matrix metalloproteinase ( MMP ) -2 , whereas it had little effect on MMP-9 , suggesting MMP-2 up-regulation by MKK6-p38 pathway as a key step for H-Ras-induced invasion and migration .
10		We also provide evidence for cross-talk among the Rac , Raf , and phosphatidylinositol 3 - kinase pathways critical for regulation of MMP-2 and MMP-9 expression and invasive phenotype .
11		Taken together , the present study elucidated the role of the Rac-MKK3/6-p38 pathway leading to H-Ras-specific induction of malignant progression in breast epithelial cells , providing implications for developing therapeutic strategies for mammary carcinoma to target Ras downstream signaling molecules required for malignant cancer cell behavior but less critical for normal cell functions .

PMID: 15487700 (Cell)   Terms: in vitro
Sent#	Symbols	Sentence	Mnemonics
0		Pamidronate resistance and associated low ras levels in breast cancer cells : a role for combinatorial therapy .
1		To identify markers sensitive to inhibitors of the farnesylation pathway , we used 3 breast cancer cell lines ( SKBR-3 , MDA-175 , and MDA-231 ) to evaluate the in vitro effects of pamidronate , an inhibitor of farnesyl diphosphate synthase .
2		In response to pamidronate , there was significant inhibition of cell proliferation in MDA-231 and SKBR-3 cells , compared to MDA-175 cells .
3		This correlated with their respective basal levels of N-ras and H-ras .
4		N-ras and H-ras protein levels were both reduced in MDA-231 cells , and to lesser extent in SKBR-3 cells , following exposure to pamidronate , whereas these markers were not altered in MDA-175 cells .
5		Combinatorial therapy with pamidronate and Gleevec , an inhibitor of several tyrosine kinases ; Velcade , a proteasome inhibitor ; or rapamycin , an inhibitor of the mammalian target of rapamycin ( m-TOR ) all showed additive effects in causing proliferative inhibition in MDA-175 cells .
6		In summary , resistance to pamidronate may result from low levels of GTPase -activating proteins , such as N-ras and H-ras , in tumor cells .
7		Combinatorial therapies directed against other signaling pathways , not dependent upon ras , may be required to overcome such resistance .

PMID: 15198801 (None)   Terms: , transgenic mice, mice, mouse
Sent#	Symbols	Sentence	Mnemonics
0		Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype .
1		BACKGROUND :
2		MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in development , followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells .
3		The occurrence of tumors is accelerated in experiments that activate FGF proto-oncogenes or remove the tumor suppressor genes Pten or P53 , implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma .
4		It is not known , however , which oncogenic pathways contribute to Wnt1 -induced tumorigenesis - further experimental manipulation of these mice is needed .
5		Secondary events also appear to be required for mammary tumorigenesis in MMTV-Neu transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase .
6		METHODS :
7		cDNA or DNA from the mammary glands and mammary tumors from MMTV-Wnt1 , MMTV-Wnt1/p53-/- , MMTV-Neu transgenic mice , and newly generated MMTV-Wnt1/MMTV-Neu bitransgenic mice , was sequenced to seek activating mutations in H-Ras , K-Ras , and N-Ras genes , or in the MMTV-Neu transgene .
8		In addition , tumors from bitransgenic animals were examined to determine the cellular phenotype .
9		RESULTS :
10	Μ	We found activating mutations at codons 12 , 13 , and 61 of H-Ras in just over half of the mammary tumors in MMTV-Wnt1 transgenic mice , and we confirmed the high frequency of activating mutations of Neu in tumors in MMTV-Neu transgenic mice .
11	Μ	Tumors appeared earlier in bitransgenic MMTV-Wnt1/MMTV-Neu mice , but no Ras or MMTV-Neu mutations were found in these tumors , which were phenotypically similar to those arising in MMTV-Wnt1 mice .
12	Μ	In addition , no Ras mutations were found in the mammary tumors that arise in MMTV-Wnt1 transgenic mice lacking an intact P53 gene .
13		CONCLUSIONS :
14		Tumorigenic properties of cells undergoing functionally significant secondary mutations in H-Ras or the MMTV-Neu transgene allow selection of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice , respectively .
15		Alternative sources of oncogenic potential , such as a second transgenic oncogene or deficiency of a tumor suppressor gene , can obviate the selective power of those secondary mutations .
16		These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype .

PMID: 14500381 (Patient)   Terms:
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0		p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells .
1		BACKGROUND :
2		The aim of this study was to evaluate expression of the bcl-2 family of apoptosis regulating proteins in normal and diseased human pancreatic tissues .
3		METHOD :
4		Expression of bcl-2 , bax , bcl-x , bak and p53 was determined in formalin-fixed paraffin wax-embedded archival specimens of normal pancreatic tissue ( n = 7 ) , chronic pancreatitis ( n = 7 ) , pancreatic ductal adenocarcinoma ( n = 23 ) and ampullary cancer ( n = 7 ) by immunohistochemistry using specific antibodies .
5		RESULTS :
6		In normal pancreas and chronic pancreatitis tissues , bcl-2 , bax and bcl-x were predominantly expressed in ductal epithelial cells while p53 was not detected .
7	Μ	In pancreatic ductal adenocarcinoma and ampullary cancer , bcl-2 was not detected compared with expression seen in normal acini ( p <001 ) , minor ( p <0001 ) and major ducts ( p <001 ) , bax expression was reduced with respect to minor ducts ( p <001 ) but no different from normal acini or major ducts .
8		bak and bcl-x were more strongly expressed in malignant epithelia compared with acini and major ducts but reduced when compared with minor ducts ( p <001 ) .
9		Overexpression of p53 was identified in 11 ( 48% ) of 23 pancreatic adenocarcinomas and 4 ( 57% ) of 7 ampullary cancers .
10	✓	Differential survival of individual patients was predicted by the relative level of bcl-x expression but not bax or bak , such that strong expression of bcl-x was associated with a median postoperative survival of 171 days when compared with 912 days for diminished expression ( p <0001 ) of bcl-x .	GE-REG-RO
11		CONCLUSION :
12		Pancreatic and ampullary cancer are associated with absent bcl-2 expression .
13		bax , bak and bcl-x expression was reduced compared with normal minor ducts whilst bak and bcl-x expression was increased when compared with major ducts .
14	✓	bcl-x expression correlates with survival following resection and may represent a potential prognosis marker .	GE-ASS-RO

PMID: 12790777 (Cell)   Terms: in vivo, In vitro, animal models, transgenic mice, mice
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0		Melatonin and mammary cancer : a short review .
1		Melatonin is an indolic hormone produced mainly by the pineal gland .
2		The former hypothesis of its possible role in mammary cancer development was based on the evidence that melatonin down-regulates some of the pituitary and gonadal hormones that control mammary gland development and which are also responsible for the growth of hormone -dependent mammary tumors .
3		Furthermore , melatonin could act directly on tumoral cells , as a naturally occurring antiestrogen , thereby influencing their proliferative rate .
4	Μ	The first reports revealed a low plasmatic melatonin concentration in women with estrogen receptor ( ER )- positive breast tumors .
5		However , later studies on the possible role of melatonin on human breast cancer have been scarce and mostly of an epidemiological type .
6		These studies described a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impairment .
7		Since light inhibits melatonin secretion , the relative increase in the melatonin circulating levels in women with a decreased light input could be interpreted as proof of the protective role of melatonin on mammary carcinogenesis .
8		From in vivo studies on animal models of chemically induced mammary tumorigenesis , the general conclusion is that experimental manipulations activating the pineal gland or the administration of melatonin lengthens the latency and reduces the incidence and growth rate of mammary tumors , while pinealectomy usually has the opposite effects .
9		Melatonin also reduces the incidence of spontaneous mammary tumors in different kinds of transgenic mice ( c-neu and N-ras ) and mice from strains with a high tumoral incidence .
10	Μ	In vitro experiments , carried out with the ER-positive MCF-7 human breast cancer cells , demonstrated that melatonin , at a physiological concentration ( 1 nM ) and in the presence of serum or estradiol : (a) inhibits , in a reversible way , cell proliferation , (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle , and (c) reduces the metastasic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness ; this effect is mediated , atleast in part , by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and beta(1)- integrin .
11		The direct oncostatic effects of melatonin depends on its interaction with the tumor cell estrogen-responsive pathway .
12	Μ	In this sense it has been demonstrated that melatonin down-regulates the expression of ERalpha and inhibits the binding of the estradiol-ER complex to the estrogen response element ( ERE ) in the DNA .
13		The characteristics of melatonin's oncostatic actions , comprising different aspects of tumor biology as well as the physiological doses at which the effect is accomplished , give special value to these findings and encourage clinical studies on the possible therapeutic value of melatonin on breast cancer .

PMID: 12727204 (Cell)   Terms: in vivo
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0		Ca2+/calmodulin binds and dissociates K-RasB from membrane .
1		We have investigated the interaction of calmodulin ( CaM ) with Ras-p21 and the significance of this association .
2		All Ras-p21 isoforms tested ( H - , K - , and N-Ras ) were detected in the particulate fraction of human platelets and MCF-7 cells , a human breast cancer cell line .
3		In MCF-7 cells , H - and N-Ras were also detected in the cytosolic fraction .
4		K-RasB from platelet and MCF-7 cell lysates was found to bind CaM in a Ca2+ -dependent but GTPgammaS-independent manner .
5		The yeast two - hybrid analysis demonstrated that K-RasB binds to CaM in vivo .
6		Incubation of isolated membranes from platelet and MCF-7 cells with CaM caused dissociation of only K-RasB from membranes in a Ca2+ -dependent manner .
7		CaM antagonist , W7 , inhibited dissociation of K-RasB .
8		Addition of platelet or MCF-7 cytosol alone to isolated platelet membranes did not cause dissociation of K-RasB and only addition of exogenous CaM caused dissociation .
9		The results suggest a potential role for Ca2+/CaM in the regulation of K-RasB function .

PMID: 12494871 (Patient)   Terms: in vivo
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0		Flow cytometric analysis of DMBA -induced early in vivo ras expression .
1		AIMS AND METHODS :
2		Digestive stromal tumors are the most frequent undifferentiated mesenchymal tumors .
3		The prognosis of these tumors is difficult to predict and the histogenesis is still subject to controversy .
4		However , the frequent and specific expression of CD117 (c-kit) by these tumors could suggest an origin from interstitial cells of Cajal .
5		The aim of this study was to analyse the histological and immunohistochemical characteristics of 46 digestive stromal tumors surgically resected , with comparaison of CD34 and CD117 expression in these tumors .
6		Sixteen tumors were analyzed on electron microscopy .
7		RESULTS :
8		Sixty three and 74% of the stromal tumors were positive for CD117 and CD34 respectively .
9		While CD117 expression was similar in all locations , on the contrary , there was a decreasing gradient of CD34 expression between gastric ( 87% ) and jejunal ( 33% ) tumors .
10		All tumors with skeinoid fibers expressed CD117 .
11		Focal expression of smooth muscle actin was noted in 43% of the cases .
12		The ultrastructural study showed no correlation with the immunohistochemical results .
13		CONCLUSION :
14		Digestive stromal tumors show an immunophenotypic and ultrastructural heterogeneity .
15		CD117 expression is frequent , but not constant .

PMID: 12165863 (Patient)   Terms: , mice, mouse models, mouse
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0		Frequent mutations of the Trp53 , Hras1 and beta-catenin ( Catnb ) genes in 1,3-butadiene -induced mammary adenocarcinomas in B6C3F1 mice .
1		DNAs from 1,3-butadiene -induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene , the ras gene family and several components of the Wnt signaling pathway , including beta-catenin ( Catnb ) , Apc and Axin .
2	Μ	Trp53 mutations were detected in 41% ( 7 out of 17 ) of tumors .
3		Each tumor with a Trp53 mutation also exhibited loss of the wild-type Trp53 allele , supporting the importance of Trp53 inactivation during development of these tumors .
4	Μ	Analyses of the Hras1 , Kras2 and Nras proto-oncogenes revealed Hras1 mutations in 53% ( 9 out of 17 ) of tumors .
5		Seven of these mutations were a G-->C transversion in Hras1 codon 13 , consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types .
6	Μ	Mutation screens in Catnb exon 2 , the Apc mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 ( 18% ) tumors .
7	Μ	In total , mutations of the Trp53 , Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene -induced mammary adenocarcinomas .
8		These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors , and that studies in mouse models may help to understand the etiology of human breast cancers .

PMID: 11705875 (Patient)   Terms: xenograft, mice
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0		Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer .
1		Antitumor and pharmacodynamic studies were performed in MCF-7 human breast cancer cells and companion xenografts with the farnesyl protein transferase inhibitor , R115777 , presently undergoing Phase II clinical trials , including in breast cancer .
2		R115777 inhibited growth of MCF-7 cells in vitro with an IC ( 50 ) of 0.31 +/- 0.25 microM .
3		Exposure of MCF-7 cells to increasing concentrations of R115777 for 24 h resulted in the inhibition of protein farnesylation , as indicated by the appearance of prelamin A at concentrations >1 microM .
4		After continuous exposure to 2 microM R115777 , prelamin A levels peaked at 2 h post drug exposure and remained high for up to 72 h .
5		R115777 administered p .
6		o .
7		twice daily for 10 consecutive days to mice bearing established s .
8		c .
9		MCF-7 xenografts induced tumor inhibition at a dose of 25 mg/kg [percentage of treated versus control ( % T/C ) = 63% at day 21] .
10		Greater inhibition was observed at doses of 50 mg/kg ( % T/C at day 21 = 38% ) or 100 mg/kg ( % T/C at day 21 = 43% ) .
11		The antitumor effect appeared to be mainly cytostatic with little evidence of tumor shrinkage to less than the starting volume .
12		Tumor response correlated with an increase in the appearance of prelamin A , but no changes in the prenylation of lamin B , heat shock protein 40 , or N-Ras were detectable .
13	Μ	In addition , significant increases in apoptotic index and p21 ( WAF1/CIP1 ) expression were observed , concomitant with a decrease in proliferation as measured by Ki-67 staining .
14		An increase in prelamin A was also observed in peripheral blood lymphocytes in a breast cancer patient who responded to R115777 .
15		These data show that R115777 possesses preclinical antitumor activity against human breast cancer and that the appearance of prelamin A may provide a sensitive and convenient pharmacodynamic marker of inhibition of prenylation and/or response .

PMID: 11467446 (None)   Terms: in vivo, in vitro
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0		The ras signaling pathway in mammary tumorigenesis and metastasis .
1		The Ras superfamily of GTPases act as important regulatory switches to co-ordinate extracellular stimuli with activation of intracellular signaling pathways and appropriate biological responses .
2		The Ras branch of this superfamily includes H - , K - and N-Ras , which are commonly mutated in particular human cancers , but notably not in those of the breast .
3		Instead , in breast cancer the signaling pathways involving these GTPases may be upregulated due to increased coupling to growth factor receptors or other tyrosine kinases commonly overexpressed in this disease , or increased expression of regulators , the Ras protein itself , or downstream effectors .
4		Functional studies utilizing both in vitro and in vivo models demonstrate that Ras signaling can regulate a variety of endpoints relevant to breast cancer progression , including anchorage dependent and independent growth , tumorigenesis , steroid sensitivity and invasion .
5		Finally , analysis of the processing and signaling mechanisms of the Ras superfamily has identified potential targets for therapeutic intervention .

PMID: 11434870 (None)   Terms:
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0		Inducible transgenics . New lessons on events governing the induction and commitment in mammary tumorigenesis .
1		Breast cancer arises from multiple genetic events that together contribute to the established , irreversible malignant phenotype .
2		The development of inducible tissue -specific transgenics has allowed a careful dissection of the events required for induction and subsequent maintenance of tumorigenesis .
3		Mammary gland targeted expression of oncogenic Ras or c-Myc is sufficient for the induction of mammary gland tumorigenesis in the rodent , and when overexpressed together the rate of tumor onset is substantially enhanced .
4		In an exciting recent finding , D'Cruz et al discovered tetracycline -regulated c-Myc overexpression in the mammary gland induced invasive mammary tumors that regressed upon withdrawal of c-Myc expression .
5	Μ	Almost one-half of the c-Myc-induced tumors harbored K-ras or N-ras gene point mutations , correlating with tumor persistence on withdrawal of c-Myc transgene expression .
6		These findings suggest maintenance of tumorigenesis may involve a second mutation within the Ras pathway .

PMID: 10825141 (None)   Terms: , transgenic mice, mice, tumor xenografts, mouse, mouse mammary tumor, tumor growth in this model
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0		Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl : protein transferase inhibitor .
1		For Ras oncoproteins to transform mammalian cells , they must be posttranslationally modified with a farnesyl group in a reaction catalyzed by the enzyme farnesyl : protein transferase ( FPTase ) .
2		Inhibitors of FPTase have therefore been developed as potential anticancer agents .
3		These compounds reverse many of the malignant phenotypes of Ras-transformed cells in culture and inhibit the growth of tumor xenografts in nude mice .
4		Furthermore , the FPTase inhibitor ( FTI ) L-744,832 causes tumor regression in mouse mammary tumor virus ( MMTV ) -v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice .
5	Μ	Although these data support the further development of FTIs , it should be noted that Ki-ras is the ras gene most frequently mutated in human cancers .
6		Moreover , Ki-RasB binds more tightly to FPTase than either Ha - or N-Ras , and thus higher concentrations of FTIs that are competitive with the protein substrate may be required to inhibit Ki-Ras processing .
7		Given the unique biochemical and biological features of Ki-RasB , it is important to evaluate the efficacy of FTIs or any other modulator of oncogenic Ras function in model systems expressing this Ras oncoprotein .
8	Μ	We have developed strains of transgenic mice carrying the human Ki-rasB cDNA with an activating mutation ( G12V ) under the control of the MMTV enhancer/promoter .
9		The predominant pathological feature that develops in these mice is the stochastic appearance of mammary adenocarcinomas .
10	Μ	High levels of the Ki-rasB transgene RNA are detected in these tumors .
11		Treatment of MMTV-Ki-rasB mice with L-744,832 caused inhibition of tumor growth in the absence of systemic toxicity .
12		Although FPTase activity was inhibited in tumors from the treated mice , unprocessed Ki-RasB was not detected .
13		These results demonstrate the utility of the MMTV-Ki-rasB transgenic mice for testing potential anticancer agents .
14		Additionally , the data suggest that although the FTI L-744,832 can inhibit tumor growth in this model , Ki-Ras may not be the sole mediator of the biological effects of the FTI .

PMID: 10629074 (None)   Terms: , rat
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0		H-ras , but not N-ras , induces an invasive phenotype in human breast epithelial cells : a role for MMP-2 in the H-ras-induced invasive phenotype .
1		Elevated p21ras expression is associated with tumor aggressiveness in breast cancer including the extent of invasion into fat tissues , infiltration into lymphatic vessels and tumor recurrence .
2		In the present study , we have examined the roles of H-ras and N-ras , members of the human ras gene family , in the pathogenesis of breast cancer .
3		We show that H-ras , but not N-ras , induces an invasive phenotype in human breast epithelial cells (MCF10A) as determined by the Matrigel invasion assay , whereas both H-ras and N-ras induce anchorage -independent growth , as shown by soft agar assay .
4		We examined the effects of H-ras and N-ras activation on the expression of MMP-2 and MMP-9 , which can degrade type IV collagen , the major structural collagen of the basement membrane .
5		We show that MMP-2 is efficiently induced by H-ras , whereas MMP-9 induction is more prominent in N-ras-activated MCF10A cells .
6		We also show that H-ras-mediated invasiveness is significantly inhibited when the expression of MMP-2 is down-regulated , using an oligodeoxyribonucleotide complementary to the MMP-2 mRNA , or when MMP-2 activity is blocked by its inhibitor TIMP-2 ( tissue inhibitors of matrix metalloproteinase-2 ) .
7		Our results show that the H-ras-induced invasive phenotype is associated more closely with the expression of MMP-2 in human breast epithelial cells , rather than the induction of MMP-9 expression , as shown previously for rat embryonic fibroblasts .

PMID: 10214865 (Patient)   Terms: in vitro
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0		Lack of constitutive activation of MAP kinase pathway in human acute myeloid leukemia cells with N-Ras mutation .
1		Mitogen -activated protein ( MAP ) kinases act as transducers of extracellular signaling via tyrosine kinase -growth factor receptors and G-protein -linked receptors to transcription factors .
2		Constitutive activation of MAP kinase has been observed in a variety of solid tumors including renal cancer and breast cancer .
3		Recently , we have reported that constitutively activated MAP kinase was observed in 50% of human primary acute myeloid leukemia ( AML ) cells .
4		Ras is one of the components of G - proteins and transduces the signal from cytokine receptors to raf-1 theoretically resulting in the activation of MAP kinase pathway .
5		In the present study , we have examined the correlation of Ras mutations and the activation of MAP kinase pathway in patients with AML .
6		Twenty out of 22 AML cases with activating N-Ras mutations showed no phosphorylated forms of ERK2 .
7		ERK2 phosphorylation was tightly correlated with ERK1 phosphorylation and MAP kinase activity detected by in vitro kinase assay .
8		Three samples with N-Ras mutations were stimulated with IL-3 , GM-CSF and G-CSF separately but ERK2 activation was induced in none of these samples stimulated with these cytokines .
9		In contrast , ERK2 was constitutively activated in all of four pancreatic carcinoma cases with K-Ras mutation at codon 12 .
10		These results suggest that function of the Ras mutations may be different between solid tumors , such as pancreatic carcinoma and colorectal carcinoma , and AML .
11		Mutated Ras does not always stimulate MAP kinase pathway constitutively and may rather inhibit classical MAP kinase cascade in AML blasts from leukemia patients .

PMID: 9823318 (None)   Terms: , rat
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0		Harvey ras results in a higher frequency of mammary carcinomas than Kirsten ras after direct retroviral transfer into the rat mammary gland .
1		Melanoma , the most aggressive form of skin cancer , results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments .
2		Cutaneous melanoma is often initiated by solar ultraviolet radiation ( UVR )- induced mutations .
3		Melanocytes intimately interact with keratinocytes , which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation .
4		Keratinocyte-derived melanocortins activate melanocortin-1 receptor ( MC1R ) to protect melanocytes from the carcinogenic effect of UVR .
5		Accordingly , MC1R is a major determinant of susceptibility to melanoma .
6		Despite extensive phenotypic heterogeneity and high mutation loads , the molecular basis of melanomagenesis and the molecules mediating the crosstalk between melanoma and stromal cells are relatively well understood .
7		Mutations of intracellular effectors of receptor tyrosine kinase ( RTK ) signalling , notably NRAS and BRAF , are major driver events more frequent than mutations in RTKs .
8		Nevertheless , melanomas often display aberrant signalling from RTKs such as KIT , ERRB1-4 , FGFR , MET and PDGFR , which contribute to disease progression and resistance to targeted therapies .
9		Progress has also been made to unravel the role of the tumour secretome in preparing the metastatic niche .
10		However , key aspects of the melanoma-stroma interplay , such as the molecular determinants of dormancy , remain poorly understood .

PMID: 9703274 (Cell)   Terms: in vivo
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0		Ras-related TC21 is activated by mutation in a breast cancer cell line , but infrequently in breast carcinomas in vivo .
1	Μ	Activating ras mutations are found in many types of human tumour .
2		Mutations in Harvey (H-) , Kirsten (K-) and neuronal (N-) ras are , however , rarely found in breast carcinomas .
3	Μ	TC21 is a ras family member that shares close homology to H - , K - and N-ras , and activating mutations have been found in ovarian carcinoma and leiomyosarcoma cell lines .
4		We have examined panels of cDNAs from breast , ovarian and cervical cell lines , and primary and metastatic breast tumours for mutations in TC21 using a single-strand conformational polymorphism ( SSCP )- based assay .
5		One breast cancer cell line , CAL51 , exhibited an altered SSCP pattern , compared with normal tissue , which was due to an A-T base change in codon 72 , causing a predicted Gln-Leu activating mutation .
6		Of nine primary and 15 metastatic breast tumour cDNAs analysed , none exhibited an altered pattern by SSCP .
7		The apparently wild-type pattern by SSCP analysis was confirmed by sequence analysis of some of the cDNAs assayed .
8		Thus , we conclude that mutations in TC21 are uncommon in breast carcinomas .

PMID: 9515813 (Cell)   Terms: in vivo, in vitro, transgenic mice, mice
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0		Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice .
1		We tested the antineoplastic effect of the farnesyltransferase inhibitor L-744,832 in mammary and lymphoid tumors overexpressing the N-ras proto-oncogene in transgenic mice .
2		Mice bearing mammary tumors were randomly assigned to receive daily 40 mg/kg s .
3		c .
4		injections of this compound ( experimental group , n = 6 ) or vehicle ( control group , n = 6 ) per day for 5.5 weeks .
5		Treatment with the compound significantly reduced the mammary tumor mean growth rate in the experimental group ( -07 mm3/day ) , as compared with the control group ( +282 mm3/day ; P <0001 ) .
6		There was a significant difference in lymphoma incidence at the end of the treatment between the experimental ( 0 of 6 ) and the control ( 3 of 6 ) groups ( P <005 ) .
7		Therefore , this compound is effective in treating in vivo mammary carcinomas and lymphomas in which an activated N-Ras pathway drives tumorigenesis .
8		The number of apoptotic figures in mammary tumors was significantly higher ( P = 004 ) in the experimental ( 147 +/- 81 ) than it was in the control ( 57 +/- 35 ) group , indicating that apoptotic induction could contribute to the mechanism of antitumor activity of this compound .
9		We analyzed the level of processing of N-Ras and H-Ras after immunoprecipitation and Western blotting of protein extracts obtained from mammary tumors treated with L-744,832 or vehicle , either in vivo or in vitro ( after primary culture of the same tumors ) , and from several in vitro treated control cell lines .
10		In all compound -treated mammary tumors and cell lines , H-Ras was mostly unprocessed ( more so after in vitro than after in vivo treatment ) , whereas N-Ras remained mostly processed .
11		Both H-Ras and N-Ras remained fully processed in all vehicle-treated samples .
12		These findings are consistent with a less intense antineoplastic effect of the treatment with the compound in our N-ras model than the effect previously reported for the same compound in H-ras transgenics .
13		In addition , the finding that , in compound -treated mammary tumors , the N-Ras protein remains mainly processed suggests that , in our model , other proteins in addition to Ras may be a target for the compound .
14		Our results and the previous findings of frequent N-ras activation in human hematopoietic malignancies support a role for L-744,832 in the treatment of lymphomas and of mammary carcinomas with an activated N-Ras pathway , as well as the testing of a farnesyl protein transferase inhibitor in humans to establish its clinical relevance .

PMID: 9442248 (None)   Terms:
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0		Cytogenetic alterations in eight mammary tumors and tumor-suppressor gene p53 mutation in one mammary tumor from dogs .
1		OBJECTIVE :
2	Μ	To identify mutations in canine mammary tumors .
3		ANIMALS : 10 tumor-bearing dogs .
4		PROCEDURE : Culture of neoplastic cells originating from mammary tumors was performed , and trypsin-G banding was used for cytogenetic investigations .
5		The same tumors were subjected to molecular genetic screening by use of DNA extraction , polymerase chain reaction , DNA elution , and DNA sequencing for ras oncogenes and the p53 tumor suppressor gene .
6		RESULTS :
7	Μ	A broad spectrum of chromosome aberrations was observed , including trisomies , reciprocal translocations , and structural and numerical X - chromosome alterations and deletions .
8	Μ	Molecular genetic analysis revealed a tumor suppressor p53 gene mutation in codon 249 of exon 7 in one instance .
9	Μ	Interestingly , analyzed mammary tumors were free of mutations in N-ras , K-ras and H-ras , exons 1 and 2 .
10		CONCLUSIONS :
11	Μ	Chromosome alterations are wide-spread in canine mammary tumors , but no ras family mutations were detected in tumors from these 10 dogs .
12		CLINICAL RELEVANCE : Knowledge about chromosome , oncogene , and tumor suppressor gene damage could be helpful for diagnosis and prognosis of neoplastic diseases in dogs .

PMID: 9264342 (None)   Terms: , transgenic mice, mice, mouse mammary tumor
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0		Histopathological features of the Harderian glands in transgenic mice carrying MMTV/N-ras protooncogene .
1		The Harderian gland is a tubule-alveolar gland found within the orbit , on the posterior aspect of the eyeball .
2		In mice , it is composed almost exclusively of secretory tubules and alveoli .
3		The Harderian glands of transgenic mice , carrying the activated N-ras oncogene under the transcriptional control of the mouse mammary tumor virus long terminal repeat promoter ( MMTV-LTR ) , were examined and compared to those of normal mice .
4		Thirty transgenic mice provided by A .
5		Pellicer ( NYU ) and 30 normal mice were examined in this study .
6		Harderian glands were dissected , immersed in a formalin-based fixative , and embedded in paraffin .
7		The sections of these glands were studied via histological techniques .
8		Our results show that proliferative alterations in the Harderian glands of these transgenic mice are present even in the youngest animals .
9		Such alterations correspond to different tumoral evolution stages , ranging from hyperplasia to wide tissue destruction .
10		In the most advanced situations , these changes are accompanied by a glandular hypertrophy .
11		Our results suggest a very high tumoral incidence in the Harderian glands of transgenic mice compared to normal mice .
12		Tumors appear spontaneously in some areas , but not at the same time in the whole gland .

PMID: 9181520 (Patient)   Terms: , transgenic mice, mice, mouse, transgenic female virgin mice
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0		Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-ras proto-oncogene .
1		The oncostatic effects of melatonin on the mammary gland have been studied in transgenic mice carrying the N-ras proto-oncogene under the control of the MMTV-LTR .
2		Female ( 4-week-old ) virgin mice with positive transgenic pedigrees were injected with melatonin ( 200 micrograms/mouse/ day , five times a week ) or vehicle late in the evening .
3		After 5 months of treatment , animals were sacrificed and the mammary glands were dissected for whole mounts , histology , and immunohistochemical analysis with a mouse monoclonal antibody specific for N-ras protein .
4		Mammary glands of control transgenic mice showed different densities of hyperplastic alveolar nodules ( HANs ) consisting primarily of dysplastic epithelial cells with nuclear atypia and prominent nucleoli .
5	Μ	The epithelial cells of HANs showed a high expression of N-ras while no immunostaining was detected in the unaffected mammary parenchyma .
6		Only one ( 10% ) of the control transgenic mice presented an infiltrating ductal carcinoma with the neoplastic cells overexpressing N-ras protein .
7		The mammary glands of melatonin treated mice had a lower density of HANs , absence of epithelial dysplastic cells , and weak immunostaining of N-ras protein in comparison to the vehicle-treated group .
8		None of the melatonin treated animals developed mammary carcinomas during the observation period .
9		The lymph nodes of the inguinal mammary glands of all the vehicle-treated transgenic mice presented hyperplasia and two animals even had lymphomas , whereas in melatonin-treated animals there was less hyperplasia ( two cases were atrophic ) and a lack of lymphomas .
10		We conclude that in the mammary glands of MMTV-LTR/N-ras transgenic female virgin mice , melatonin a ) reduces the incidence of HANs and the expression of N-ras protein in focal hyperplastic lesions , b ) completely prevents the development of epithelial cell atypia and mammary adenocarcinomas , and c ) also reduces the hyperplasia of the mammary lymphoid tissue and prevents the development of lymphomas .

PMID: 9067556 (Patient)   Terms: , mice, mouse
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0		Induction of mammary cancer and lymphoma by multiple , low oral doses of 7,12-dimethylbenz[a]anthracene in SENCAR mice .
1		Existing models of mouse mammary carcinogenesis induced by the model polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene ( DMBA ) typically use a small number of bolus doses applied intragastrically .
2		In contrast to this , typical human exposures to carcinogens are thought to be at lower doses and to occur with chronic or sporadic timing .
3		When the classical dosage ( 1 mg DMBA given once a week for 6 weeks ) was split into five daily doses of 200 microg given intragastrically to female SENCAR mice each week for 6 weeks , toxicity was high and the major tumor type seen was lymphoma .
4		Lowering the dose to 60 microg/day gave less toxicity , a 75% incidence of lymphoma and a 30% incidence of mammary carcinoma .
5		However , 20 microg DMBA given five times per week for 6 weeks resulted in a 65-70% incidence of mammary carcinoma within approximately 50 weeks .
6		This represents a 50-fold lower daily dosage of DMBA than that used in the classical model .
7		DNA was prepared from 10 mammary adenocarcinomas and 10 lymphomas and exons 1 and 2 of the H-ras1 , K-ras and N-ras genes were sequenced using PCR techniques .
8		Mutations altering codons 12 or 61 of one of the ras family genes were found in 4/10 mammary carcinomas and 5/10 lymphomas .
9		Three mammary tumors exhibited codon 61 mutations , one in each of the genes studied , and a fourth tumor contained a codon 12 mutation in the K-ras gene .
10		Among the lymphomas , two mutations in codon 12 of K-ras , one mutation in codon 61 of K-ras and two mutations in codon 61 of N-ras were also found .
11		Each of the mutations could be interpreted as a G-->T or A-->T transversion .
12		It is suggested that the high incidence of lymphoma at the higher , repetitive doses may be related to immunotoxicity .
13		These low dose models of lymphomagenesis and mammary carcinogenesis should prove useful for tests of chemopreventive agents that target the initiation phase of carcinogenesis .

PMID: 8806695 (None)   Terms: in vivo, transgenic mice, mice, mouse mammary tumor
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0		Activated N-ras oncogene and N-ras proto-oncogene act through the same pathway for in vivo tumorigenesis .
1		We compared the tumorigenic effects of the N-ras oncogene and the N-ras proto-oncogene in lymphoid and mammary tissues in an in vivo model .
2		For this purpose , we generated transgenic mice with high levels of N-ras oncogene or N-ras proto - oncogene expression , driven by the complete mouse mammary tumor virus LTR ( MMTV-LTR ) ( MMTV/N-rasT and MMTV/N-rasN constructs ) and transgenic mice with low levels of N-ras oncogene or N-ras proto - oncogene expression , driven by a truncated MMTV-LTR ( TMTV/N-rasT and TMTV/N-rasN constructs ) .
3		We show that both , the N-ras proto-oncogene and the N-ras oncogene with a C : G-->A : T mutation at codon 61 , lead to identical tumor types : lymphoblastic T - cell lymphomas , cleaved B - cell lymphomas and poorly differentiated mammary carcinomas .
4		Nevertheless , there were quantitative differences in tumor incidence and latency and in transgene expression among N-ras oncogene and N-ras proto - oncogene transgenics .
5		Despite these differences in tumor kinetics , the predisposition to identical tumor types is in agreement with the idea that the N-ras oncogene and the N-ras proto-oncogene act through the same pathway for in vivo tumorigenesis in B - cells , T - cells or mammary epithelial cells .

PMID: 7493356 (Patient)   Terms: xenograft, mice, tumor model
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0		Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression .
1		Radioimmunotherapy ( RIT ) in breast cancer patients using I-131-chimeric L6 ( ChL6 ) and in human breast cancer xenografts in nude mice using Y-90-1,4,7,10-tetraazacylododecant N , N' , N" , N"'-tetraacetic acid - peptide ChL6 ( Y-90-ChL6 ) has shown promise .
2		Tumor cell response to low-dose rate ( 5-25 rads/h ) irradiation from Y-90-ChL6 RIT , therefore , was correlated with levels of tumor cell mRNA for selected genes linked to programmed cell death ( apoptosis ) .
3		Three groups of 10-16 mice with 1-2 HBT 3477 xenograft tumors were treated with 100 , 150 , or 250 microCi Y-90-ChL6 .
4		Three tumors were taken before and two tumors each were taken 3 , 6 , and 24 h after injection of 150 microCi Y-90-ChL6 .
5		Tumor expression of mRNA was amplified by PCR for p53 , PIC1 , c-myc , and transforming growth factor -beta 1 ; quantitated ; and standardized to N-ras .
6		Tumors received radiation doses of 2000 , 3000 , and 5000 rads , respectively , for the groups of mice that received 100 , 150 , and 250 microCi Y-90-ChL6 , and tumor regression occurred in each group , with mean tumor volumes decreased by 10 , 50 , and 95% at nadir after Y-90-ChL6 injection .
7		At the highest dose level , 30% of mice had complete remissions , and no treatment deaths occurred , although tumors subsequently recurred .
8	Μ	Continuous up-regulation of transforming growth factor -beta 1 and c-myc mRNA expression was observed from 3 to 24 h after treatment .
9		Expression of p53 and PIC1 increased at 3 h and subsequently decreased to the untreated control levels .
10		These observations are consistent with previous observations of early responses of p53 and PIC1 to cellular DNA damage and subsequent G1 cell cycle arrest or apoptosis .
11	Μ	Apoptosis-associated gene expression patterns observed in this tumor model provide evidence that changes are initiated in the first 24 h of RIT associated with radiation doses of 100-700 rads .
12		These preliminary data suggest that insight into the molecular basis of RIT -induced tumor regression may be gained by further studies using different radiation doses .

PMID: 7576104 (None)   Terms: , transgenic mice, mice, mouse mammary tumor
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0		Promoter demethylation in MMTV/N-rasN transgenic mice required for transgene expression and tumorigenesis .
1		We studied demethylation within the transgene promoter in transgenic mice carrying the N-ras proto-oncogene driven by the mouse mammary tumor long terminal repeat ( MMTV/N-rasN ) and the relationship of demethylation to transgene overexpression and tumorigenesis .
2		Demethylation at Fspl or Clal sites correlated with age of the animal and transgene expression in nontumorous mammary gland .
3		Demethylation preceded expression in this tissue .
4		In lymphomas and mammary tumors , the promoter Fspl and Clal sites were significantly more demethylated than in nontumorous control tissues .
5		The Aval , Cfol , and Hpall sites were also found to be undermethylated in older animals and showed differences between tumor and control tissues .
6		Two additional sites ( Eagl and Narl ) remained fully methylated in all tissues .
7		In contrast with normal tissue , demethylation at the Fspl and Clal sites and expression were not correlated in tumor tissue .
8	Μ	An increase in expression in normal tissue initially occurred and was correlated with the level of promoter demethylation ; this increase was followed by a further increment in transgene expression when tumors developed .
9		Thus , promoter demethylation leading to transgene overexpression was associated with long-latency tumorigenesis in MMTV/N-rasN transgenic mice .
10		Demethylation of proto - oncogene promoters may therefore be a mechanism of carcinogenesis that requires further investigation in human tumors .

PMID: 21556624 (None)   Terms: phase i
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0		P53 alterations show significant correlation with gene amplification and s-phase index in breast-cancer .
1		Oncogenesis and classification of mixed-type liposarcoma : a radiological , histopathological and molecular biological analysis .

PMID: 7710953 (Cell)   Terms: in vitro, in vivo, mice
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0		A new human breast cancer cell line , KPL-1 secretes tumour-associated antigens and grows rapidly in female athymic nude mice .
1		We recently established a new human breast cell line , designated KPL-1 , which was derived from the malignant effusion of a patient with breast cancer .
2		This cell line is highly tumorigenic and grows rapidly in female nude mice .
3		Cytogenetic analysis indicated its human origin and revealed a hypertriploid modal number of chromosomes .
4		Electron microscopic examination suggested that the KPL-1 cells are of epithelial origin .
5		Immunohistochemical studies revealed that the cells express cytokeratin , carcinoembryonic antigen and CA 15-3 .
6		They also possess a large number of oestrogen receptors but not progesterone receptors .
7		Interestingly , KPL-1 cells seem to grow oestrogen independently in vitro .
8	Μ	No amplification of c-erbB-2 , c-myc , H-ras and N-ras genes was detected .
9		KPL-1 cells secrete a large amount of tissue polypeptide antigen ( TPA ) .
10		Although the secretion of CA 15-3 seemed to be constant throughout all cell growth phases , TPA secretion increased during the exponential growth phase and decreased during the plateau phase .
11		Serum TPA levels significantly correlated with the volume of KPL-1 tumours transplanted into nude mice .
12		These data suggest that this KPL-1 cell line may be useful for studying oestrogen -independent growth and the kinetics of tumour-associated antigens in vivo as well as in vitro .

PMID: 8712577 (Patient)   Terms:
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0		[ Ras gene analysis in mammary tumors of dogs by means of PCR-SSCP and direct genomic analysis ] .
1		The oncogenic capacities of RAS family genes ( Ha-ras , Ki-ras , and N-ras ) are usually activated by point mutations in the conserved regions ( codons 12 , 13 , and 61 ) , resulting in single amino acid substitution in the specific proteins ( p21 ) .
2		In order to verify the involvement of RAS genes in dog mammary tumors we analyzed the genomic DNA from 20 mammary tumors of dog by means of the Polymerase Chain Reaction-Single Strand Conformation Polymorphism ( PCR-SSCP ) method and the direct genomic sequencing .
3		The absence of point mutations in the "hot spots" of RAS genes suggests a lack or a low frequency of such a pattern of RAS genes activation in dog mammary tumors .
4		The results are also in agreement to what reported in human mammary tumors .
5		However , the presence of genetic alterations in other functional areas of the RAS genes or other mechanisms of activations cannot be ruled out .

PMID: 7987834 (None)   Terms: , mouse, transgenic mice, mice, Transgenic mice
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0		An overexpressed N-ras proto-oncogene cooperates with N-methylnitrosourea in mouse mammary carcinogenesis .
1		The induction of tumors with chemicals and the production of transgenic animals are two experimental approaches to study oncogene involvement in carcinogenesis .
2		The combination of both strategies offers an excellent model system to study tumor development .
3		This study analyzes the potential cooperation of N-methylnitrosourea ( MNU ) treatment and N-ras proto - oncogene overexpression in tumorigenesis in transgenic mice .
4		The overexpression of the N-ras proto-oncogene in these animals is associated with development of mammary tumors and lymphomas .
5	Μ	After MNU treatment we analyzed tumor incidence and latency , levels of transgene expression , and pattern of ras mutations in codons 12 , 13 , and 61 of H - , K - , and N-ras genes in both tumor types .
6		Transgenic mice treated with MNU had significantly ( P <0001 ) shorter latency of appearance of mammary tumors [8.6 +/- 3.0 ( SD ) months] than phosphate-buffered saline -treated transgenics ( 128 +/- 23 months ) .
7		All mammary tumors overexpressed the N-ras transgene and lacked ras mutations .
8		Moreover , MNU-treated transgenics had an incidence and latency of lymphomas similar to that of MNU-treated nontransgenic mice .
9		No significant differences in incidence of point mutations ( K-ras codon 12 or 13 and N-ras codon 61 ) in lymphomas were seen between these two groups .
10	Μ	All lymphomas overexpressed the N-ras transgene , except for those carrying a K-ras point mutation .
11		Overexpression of the N-ras proto-oncogene cooperates with non-ras genes mutated by MNU in mouse mammary carcinogenesis .
12		Conversely , N-ras proto - oncogene overexpression does not show cooperation with MNU in lymphomagenesis in our system .
13		This study suggests that proto - oncogene overexpression may be a mechanism of activation of the ras pathway , alternative to point mutation .
14		Similarly to actions for ras genes activated by point mutation , overexpression of the N-ras protooncogene predisposes to tumorigenesis and cooperates with a carcinogen in tumorigenesis .
15		The possibility that ras overexpression plays a role in human breast tumorigenesis requires active investigation .

PMID: 7927918 (Cell)   Terms:
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0		Expression of the extracellular matrix molecule thrombospondin inversely correlates with malignant progression in melanoma , lung and breast carcinoma cell lines .
1		Thrombospondin ( TSP ) is a member of a family of extracellular matrix glycoproteins that may participate in multiple aspects of the metastatic cascade .
2		We report an inverse correlation of steady-state Thbs-1 mRNA and protein expression with malignant progression among murine melanoma and human lung and breast carcinoma cell lines .
3	Μ	Murine K-1735 melanoma cell lines of low metastatic potential , including K-1735 lines transfected with the murine nm23-1 cDNA , expressed higher TSP levels than related highly metastatic lines .
4	Μ	In a model system of lung carcinoma malignant progression , immortalized human bronchial epithelial cells expressed higher TSP levels than v-Ki-ras , v-Ha-ras or n-ras transfectants , which in turn expressed higher TSP levels than tumor-derived , more aggressive variants .
5		Among 3 unrelated breast carcinoma cell lines , Thbs-1 steady-state mRNA levels were greater in the 2 non-metastatic lines than the metastatic line .
6	✓	Our data show that malignant progression in some cell lines is associated with reduced TSP expression .	RO-ASS-GE
7		The suppressive effects of nm23-1 transfection on metastatic potential are also associated with increased TSP expression ; ras transfection , which results in increased tumorigenesis , is associated with decreased TSP expression .

PMID: 8185828 (Patient)   Terms: , rat
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0		Infrequent mutation of Ha-ras and p53 in rat mammary carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine .
1		2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP ) is the most abundant of the heterocyclic amines , a group of potent carcinogens contained in cooked meat and fish .
2		Female F344 rats fed a diet containing 100 or 400 ppm PhIP developed mammary carcinomas within 104 or 52 wk , respectively , at the rate of 47% for each group ; these carcinomas were examined for mutations in three members of the ras gene family and in the p53 gene .
3	Μ	Single-strand conformation polymorphism ( SSCP ) analysis and direct sequencing demonstrated a G-->A transition at the second position of Ha-ras codon 12 , with the resultant substitution of glutamic acid for glycine , in two of 10 carcinomas induced by 100 ppm PhIP and in one of seven induced by the 400 ppm dose .
4	Μ	No mutations in Ki-ras or N-ras were detected .
5	Μ	cDNA polymerase chain reaction-SSCP analysis and direct sequencing demonstrated a G-->T transversion at the third position of p53 codon 130 , with the resultant substitution of asparagine for lysine , in one of the 10 carcinomas induced by 100 ppm of PhIP for which freshly frozen samples were available .
6		PhIP -induced rat mammary carcinogenesis can be regarded as a unique system in that rat mammary carcinomas are negative for ras and p53 mutations .

PMID: 7657520 (Patient)   Terms: , mouse, mouse mammary tumor, mouse mammary metastasis model
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0		Correlation of differences in modulation of ras expression with metastatic competence of mouse mammary tumor subpopulations .
1		The ras family of cellular oncogenes is one of the most frequently detected families of transformation-inducing genes in human solid tumors .
2		The capacity of breast cancers to grow and metastasize have been related to enhanced expression of normal p21ras rather than the mutant form .
3		Transformation in tumours that lack the mutant p21ras has been suggested to result from transcriptional deregulation of ras .
4		cis-Acting sequence elements that participate in the regulation of gene expression in normal tissues and that could serve as potential targets for the deregulation of expression in tumors have been localized in several genes including c-myc and N-ras .
5		Using a mouse mammary metastasis model system of closely related tumor subpopulations that vary in metastatic potential and with defined deficiencies , we show that c-Ha-ras plays a prominent role as a metastasis-modulating gene in this system .
6		We have identified a highly conserved cis-acting sequence element in the first intron of the mouse and rat , and in the first exon of Ha - and Ki-ras genes of human , mouse and rat .
7		This regulatory sequence confers strong transcription enhancer activity that is differentially modulated by steroid hormones in metastatic and nonmetastatic subpopulations .
8		Our results indicate that perturbations in the regulatory activities of cis-acting sequences such as the one we have identified may play an important role in governing oncogenic potency of Ha-ras through transcriptional control mechanisms .

PMID: 8102189 (Patient)   Terms:
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0		[ Aggressive diffuse lymphoma with malignant pleural effusion expressing c-erbB-2 ( neu ) oncogene products ] .
1		An 83-year-old male was admitted with a right pleural effusion and generalized lymphadenopathy .
2		Serum LDH level was elevated to 801 IU/L , and the pathological diagnosis from inguinal lymph node needle biopsy was malignant lymphoma ( ML ) of diffuse , large cell , non-cleaved type , according to the working formulation .
3		The surface phenotypes of the malignant cells from the pleural effusion were analyzed by a fluorescent-activated cell sorter with a panel of monoclonal antibodies ( MAbs ) .
4		The ML cells coexpressed antigens detected by MAbs CD10 (CALLA) , CD19 , CD20 , CD22 , CD24 , CD38 , Ia , c-neu and surface immunoglobulin G kappa .
5	Μ	A high expression of NRAS p21 was also detected by cytoplasmic immunofluorescence technique .
6		The patient died 19 days later despite a combination of chemotherapy and intensive supportive therapy .
7		From these findings it seems that c-neu may be a prognostic indicator not only for breast cancers but also for lymphoproliferative disorders .
8		Further accumulation of such cases is needed .

PMID: 1356615 (Cell)   Terms: , mice
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0		Establishment of the human BSMZ breast cancer cell line , which overexpresses the erbB-2 and c-myc genes .
1		A new cell line , designated BSMZ , was established from a malignant pleural effusion from a woman with breast cancer .
2		This line has a doubling time of 27 h and has now been cultured for over 120 passages .
3		The large , rounded BSMZ cells grow as both a monolayer and as aggregations in suspension .
4		Intracytoplasmic lumen , a finding consistent with results from cells derived from mammary tissue , was detected on ultrastructural analysis .
5		Injection of BSMZ cells into nude mice resulted in the growth of solid tumors 4 weeks after inoculation .
6		The solid tumor was identical to the original BSMZ cells in microscopic and electron microscopic studies .
7		These cells possess an average of 80 chromosomes .
8		Expression of erbB-2 and c-myc genes was increased by 10-fold , while there was no detectable overexpression of the N-ras and c-myb genes .
9	Μ	Southern analysis has revealed amplification of the erbB-2 and c-myc loci .
10		The BSMZ cell line may therefore provide a useful model for the study of human breast cancer and overexpression of the erbB-2 gene .

PMID: 1328989 (None)   Terms: , transgenic mice, mice
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0		Overexpression of the N-ras proto-oncogene , not somatic mutational activation , associated with malignant tumors in transgenic mice .
1		Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage .

PMID: 1390191 (None)   Terms: , rat, rat tumour model
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0		Ras gene mutation -independent tumours in the intestine of the rat by a single dose of N-methyl-N-nitrosourea .
1	Μ	Aiming at a sequential analysis of the role of ras gene point mutations during intestinal carcinogenesis , we established an experimental rat tumour model using N-methyl-N-nitrosourea ( MNU ) as an initiating agent as this carcinogen has been found to induce rat mammary carcinomas with a high prevalence of ras gene mutations .
2		MNU treatment of a total of 249 rats ( 25 or 50 mg/kg ip ) in various combinations with partial hepatectomy , hydroxyurea infusion and/or phenobarbital exposure resulted in a high incidence of intestinal adenomas and carcinomas of different histological types , besides liver , soft tissue and auditory sebaceous gland tumours .
3	Μ	With PCR-amplified DNA the prevalence of mutations of codon 12 and 61 of H - , K - and N-ras was determined in dot blots by hybridization with 32P-labelled allele -specific oligonucleotides .
4	Μ	Ras gene point mutations were not observed in any of the 41 intestinal rat tumours randomly selected from various experimental groups .
5	Μ	Considering the high prevalence of ras mutations in MNU -induced mammary carcinomas of the rat the observed complete lack of ras mutations in intestinal tumours induced in the rat by the same carcinogen suggests that organ -specific intraspecies differences in the mechanism of malignant transformation exist even for a heterolytically decomposing , direct acting carcinogen like MNU .

PMID: 1596892 (Patient)   Terms: , mice, mouse
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0		Activation of the Ha- , Ki- , and N-ras genes in chemically induced liver tumors from CD-1 mice .
1	Μ	We compared the profile of ras gene mutations in spontaneous CD-1 mouse liver tumors with that found in liver tumors that were induced by a single i .
2		p .
3		injection of either 7, 12-dimethylbenz(a) anthracene ( DMBA ) , 4-aminoazobenzene , N-hydroxy-2-acetylaminofluorene , or N-nitrosodiethylamine .
4	Μ	By direct sequencing of polymerase chain reaction-amplified tumor DNA , the carcinogen-induced tumors were found to have much higher frequencies of ras gene activation than spontaneous tumors .
5	Μ	Furthermore , each carcinogen caused specific types of ras mutations not detected in spontaneous tumors , including several novel mutations not previously associated with either the carcinogen or mouse hepatocarcinogenesis .
6		For example , the model compound DMBA is known to cause predominantly A to T transversions in Ha-ras codon 61 in mouse skin and mammary tumors , consistent with the ability of DMBA to form bulky adducts with adenosine .
7		Our results demonstrate that the predominant mutation caused by DMBA in mouse liver tumors is a G to C transversion in Ki-ras codon 13 ( DMBA is also known to form guanosine adducts ) , illustrating the influence of both chemical - and tissue -specific factors in determining the type of ras gene mutations in a tumor. 4-Aminoazobenzene and N-hydroxy-2-acetylaminofluorene also caused the Ki-ras codon 13 mutation .
8		In addition , we found that N-nitrosodiethylamine , 4-aminoazobenzene , and N-hydroxy-2-acetylaminofluorene all caused G to T transversions in the N-ras gene ( codons 12 or 13 ) .
9		This is the first demonstration of N-ras mutations in mouse liver tumors , establishing a role for the N-ras gene in mouse liver carcinogenesis .
10	Μ	Finally , comparison of the ras mutations detected in the direct tumor analysis with those detected after NIH3T3 cell transfection indicates that spontaneous ras mutations ( in Ha-ras codon 61 ) are often present in only a small fraction of the tumor cells , raising the possibility that they may sometimes occur as a late event in CD-1 mouse hepatocarcinogenesis .

PMID: 1657976 (Cell)   Terms: , mouse, mouse mammary tumor
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0		Enzymatic amplification involving glycosyltransferases forms the basis for the increased size of asparagine-linked glycans at the surface of NIH 3T3 cells expressing the N-ras proto-oncogene .
1		Expression of ras oncogenes in NIH 3T3 fibroblasts results in the acquisition by these cells of an invasive potential concomitant with the appearance of cell surface asparagine-linked complex -type glycan structures of a higher average molecular weight ( Bolscher , J .
2		G .
3		M. , van der Bijl , M .
4		M .
5		W. , Neefjes , J .
6		J. , Hall , A. , Smets , L .
7		A. , and Ploegh , H .
8		L. ( 1988 ) EMBO J. 7 , 3361-3368 ) .
9		We have investigated the enzymatic basis for the altered glycosylation by assessing the activities of all major Golgi glycosyltransferases involved in the synthesis of these structures .
10		Use was made of a stable transfectant cell line (T15) containing the N-ras-protooncogene under the control of a glucocorticoid-inducible mouse mammary tumor virus promoter .
11		Upon induction of the ras gene with dexamethasone : 1 ) the levels of N-acetylglucosaminyltransferase I and II were essentially unaltered , indicating an unaffected potential to synthesize complex -type glycans ; 2 ) the activities of the branching N-acetylglucosaminyltransferase III and V were elevated 2 - to 2.5-fold suggesting the formation of increased amounts of bisected glycans and of structures carrying a Gal beta 1----GlcNAc beta 1----6Man-branch ; 3 ) the levels of the elongating beta 4-galactosyltransferase and beta 3-N-acetylglucosaminyl-transferase were increased 5 - to 7-fold indicating a strongly enhanced capacity to synthesize polylactosaminoglycan chains ; 4 ) the level of the major chain -terminating enzyme , alpha 3-galactosyltransferase , was slightly decreased ( 07-fold ) , whereas those of the alpha 3 - and alpha 6-sialyltransferases were slightly elevated ( 13 - and 2-fold , respectively ) , suggesting a shift from termination by alpha-galactosyl residues to termination by sialic acid moieties .
12		Studies on the acceptor specificities of the different glycosyltransferases indicate that these changes occur in a coordinated manner in which the effects of altered glycosyltransferase expression levels amplify each other .
13		Analysis of the size of cell surface complex -type glycopeptides before and after digestion with neuraminidase and endo-beta-galactosidase suggested an increased sialic acid density , an increase in the number and/or length of polylactosaminoglycan chains , and an increased branching of the glycans upon N-ras induction .
14		The enzymatic results explain these structural changes and allow us to define the alterations in glycosylation pathways associated with ras expression .

PMID: 1660818 (None)   Terms: , mouse, mouse mammary tumor, mice
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0		The different activation of int genes in mammary carcinomas developed in three mouse strains harboring mouse mammary tumor viruses derived from DD/Tbr .
1		RNA expressions of common integration site ( int ) genes and several oncogenes were investigated in mammary carcinomas spontaneously developed in different three strains of mice ; DD/Tbr , NIH Swiss and BALB/c which harbor DD-MMTV derived from DD/Tbr mouse .
2		Latter two strains of mice were designated NIH/Mtv+ and BALB/Mtv+ , respectively .
3	Μ	An increased expression of int-1 ( wnt-1 ) and int-2 genes was observed in 56% ( 9/16 ) and 50% ( 8/16 ) of mammary carcinomas of DD/Tbr mice , respectively .
4		Either int-1 or int-2 RNAs were expressed in 81% ( 13/16 ) of the carcinomas of DD/Tbr mice .
5		IN NIH/Mtv+ mice , activation of int-1 and int-2 was observed in 41% ( 7/17 ) and 24% ( 4/17 ) of mammary carcinomas , respectively .
6		Either int-1 or int-2 RNAs were expressed in 47% ( 8/17 ) of the carcinomas examined in this strain .
7		In BALB/Mtv+ mice , on the other hand , either int-1 or int-2 gene were transcribed into RNAs at low frequency ( 33% : 3/9 ) .
8		These results suggest that the frequency of activation of int genes in mammary carcinomas induced by the same DD-MMTV in three strains of mice is genetically defined characteristics of these strains , and that the involvement of int-1 and int-2 genes in virus-induced mammary carcinogenesis may be influenced by genetic properties of animals .
9		The activation of int-1 and int-2 genes did not clearly correlate with an increase in the expression of oncogenes examined ; H-ras , K-ras , N-ras , myc , raf , fgr , fms , erB , mos , and src genes .

PMID: 27467677 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Aggressive Diffuse Lymphoma Coexpressing NRAS p21 and C-erbB-2 ( neu ) Oncogene Products , and CALL A ( CD 10 ) .
1		We describe here a case of malignant lymphoma ( ML ) which coexpressed common acute lymphoblastic leukemia antigen ( CALLA : CD10 ) and NRAS p21 and c-erbB-2 ( neu ) oncogene products .
2		The patient , an 83 year-old man , had massive generalized lymphadenopathy and pleural effusions .
3		Serum LDH levels were elevated to 801 IU/L .
4		Surface phenotypes were analysed by a fluorescent-activated cell sorter with a panel of monoclonal antibodies ( MAbs ) .
5		The ML cells coexpressed antigens detected by MAbs CD10 , CD19 , CD20 , CD22 , CD24 , CD38 , Ia ( HLA-DR ) , c-neu and surface immunoglobulin ( Ig ) G , Kappa .
6		Gene rearrangements for the Ig JH and JK were found .
7	Μ	Overexpression of NRAS p21 was shown by gene amplification using Southern blot analysis , while gene amplification of c-erbB-2 oncogene was also demonstrated .
8		To our knowledge , this is the first report to demonstrate an overexpression of p185 c-neu on ML cells .
9		These findings suggest that the p185 neu may be a prognostic indicator not only for breast adenocarcinomas but also for lymphoproliferative disorders , and that the transforming p185 protein may be involved in the mechanisms of aggressive expansion of lymphoid neoplasias .

PMID: 2064724 (Patient)   Terms:
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0		Methylation of estrogen receptor 1 in colorectal adenomas is not age -dependent , but is correlated with K-ras mutation .
1		The molecular genetics of human endometrial carcinoma have yet to be defined to any significant extent .
2		Cell lines from 11 endometrial carcinomas were examined for alterations in proto-oncogenes that might predictably be present , based on existing data from the better-characterized human carcinomas of the uterine cervix , ovary , and breast .
3		Codons 12 , 13 , and 61 of the Ha-ras , Ki-ras , and N-ras genes were examined for possible point mutations , and the c-erbB2/neu , c-myc , and epidermal growth factor receptor ( EGFR ) genes were examined for amplification or overexpression .
4	Μ	Ras mutations were found in seven of 11 ( 64% ) tumors , including three in codon 61 of Ha-ras ( CAG----CAT ) and four in codon 12 of Ki-ras ( GGT----GAT in two and GGT----GTT in two ) .
5	Μ	No evidence was found for amplification or overexpression of the c-erbB2 or EGFR genes in any tumor .
6		One tumor contained amplified c-myc sequences and exhibited relative overexpression of c-myc .
7	Μ	These data suggest that the amplification or overexpression of several proto-oncogenes frequently observed in other human gynecologic and breast tumors are not prevalent in endometrial carcinoma and that ras gene mutations are relatively common in this tumor type .

PMID: 2248738 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		[ Study of prognostic factors in patients with stage I non-small cell lung cancer ] .
1		Neoadjuvant imatinib therapy used to treat locally advanced or metastatic gastrointestinal stromal tumors ( GI ST ) remains under active investigation .
2		We studied three cases of locally advanced gastric GISTs treated with imatinib on a neoadjuvant basis , followed by a complete surgical resection .
3		Three patients were diagnosed with locally advanced unresectable GIST of the stomach and were started on imatinib 400 mg/day .
4		After the imatinib treatment , partial responses were achieved in all patients and the tumors were considered resectable .
5		Surgical resection was done after 7 , 11 , and 8 months of imatinib therapy , respectively .
6		In one case , a metastatic liver lesion was detected during the imatinib treatment using computed tomography scans , so the imatinib therapy was maintained for 11 months postoperatively .
7		In the other two patients without distant metastasis , imatinib treatment was not restarted after surgery .
8	Μ	Mutational analysis revealed a mutation in exon 11 of the c-kit gene in two patients , and wild-type c-kit and PDGFRA in one patient .
9		During pathology review of all three cases , we noted several features common to imatinib treatment .
10		There was no evidence of tumor recurrence in all three patients at respective follow-up visits of 22 , 15 , and 7 months .
11		These results suggest that the neoadjuvant imatinib therapy is a potentially curative approach for selected patients with locally advanced GIST .

PMID: 2174525 (None)   Terms: , transgenic mice, mice, Transgenic mice, mouse mammary tumor
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0		Tumorigenesis and male sterility in transgenic mice expressing a MMTV/N-ras oncogene .
1		Transgenic mice carrying the activated N-ras oncogene under the transcriptional control of the mouse mammary tumor virus ( MMTV ) long terminal repeat were produced .
2		The transgene is expressed in a tissue distribution consistent with the fact that it is driven by the MMTV-LTR , and similarly to MMTV/H-ras constructs , its presence elicits tumors in Harderian , mammary and salivary glands .
3		In addition it appears to compromise male reproductive function , which has not been described with the other ras transgenes .
4		This finding is consistent with the existence of distinct physiological actions for each of the ras family members .

PMID: 2235101 (Patient)   Terms: ex vivo
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0		Ras gene product expression in blood and marrow smears of patients with acute leukemia : importance of fixation .
1	Μ	Activation of ras protooncogenes by any of several possible mutations in codons 12 , 13 or 61 has been demonstrated in a variety of human malignancies , including acute non-lymphoblastic leukemia ( ANLL ) .
2		In situ staining for the ras gene product , p21 , has been demonstrated in carcinomas of several sites .
3		High levels of p21 expression have been associated with histologic anaplasia in prostate cancer and regional lymph node metastasis in breast cancer .
4		We examined 16 marrow aspirates and blood smears from patients with acute leukemia , predominantly ANLL , and eight controls .
5		Marrow aspirates or blood were smeared on glass slides and fixed immediately in 10% buffered formalin .
6		p21 was examined with avidin-biotin linked immunoperoxidase visualization .
7		Particular attention must be paid to antibody selection and fixation protocol to demonstrate p21 , owing to its rapid degradation ex vivo .
8		Three of 16 patients exhibited occasional high p21 expression primarily in leukemic blasts , but in no case were more than 10% of blast cells positive .
9		Normal reticuloendothelial and myeloid cells occasionally exhibited mild to moderately heavy staining , but megakaryocytes , erythroid precursors , lymphocytes and plasma cells were consistently negative .
10		Most patients , 5 normal volunteers and 3 patients with non-malignant disease , exhibited no reactivity , or only a faint blush .
11		These data suggest that while point mutation and concomitant activation of c-N-ras occurs regularly in ANLL , high levels of ras p21 expression are rarely found with this technique .

PMID: 2180965 (None)   Terms: , mouse, mouse mammary tumor
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0		Potentiation of oncogenic N-ras-induced neurite outgrowth and ornithine decarboxylase activity by phorbol dibutyrate and protein kinase inhibitor H-8 .
1		A recombinant N-ras oncogene , under the transcriptional control of a corticosteroid -inducible mouse mammary tumor virus ( MMTV ) promoter , has been stably transfected into a PC12 rat pheochromocytoma subline .
2		This cell line , designated UR61 , undergoes N-ras-induced neurite outgrowth and cessation of division when treated with dexamethasone ( Guerrero et al. : Biochemical and Biophysical Research Communications 150 : 1185-1192 , 1988 ) .
3		We have employed the UR61 cell line as a model for ras oncogene -induced neuronal differentiation .
4		In UR61 cells , dexamethasone-induced expression of the recombinant N-ras gene resulted in time -dependent expression of ornithine decarboxylase enzyme ( ODC ) activity .
5		Prompted by recent reports of possible functional ( Lacal et al. : Molecular and Cellular Biology 7 : 4146-4149 , 1987 ; Wolfman and Macara : Nature 325 : 359-361 , 1987 ) and direct ( Jeng et al. : Biochemical and Biophysical Research Communications 145 : 782-788 , 1987 ) interactions between oncogene ras-coded p21 and protein kinase C ( PK-C ; Ca++/phospholipid -dependent protein kinase ) , we employed the protein kinase inhibitor H-8 ( N-[2 - ( methylamino ) ethyl]-5-isoquinoline sulfonamide dihydrochloride ) and phorbol 12,13-dibutyrate ( PDBu ) to investigate this putative interaction in the UR61 cells , where ODC activity and neurite outgrowth were used as indicators of oncogenic N-ras action .
6		Treatment of UR61 cells with PDBu depleted cells of PK-C and failed to promote neurite outgrowth but enhanced N-ras-induced neurite outgrowth and ODC activity .
7		H-8 , which suppressed ODC induction by forskolin and phorbol myristate acetate , enhanced both N-ras-induced ODC activity and neurite outgrowth .
8		Inhibition of ODC activity by difluoromethylornithine ( DFMO ) did not suppress oncogenic ras-induced neurite outgrowth , suggesting that these two ras-triggered events are mechanistically independent .
9		These findings suggest that certain actions of N-ras can occur in cells depleted of PK-C , and thus , the role of PK-C in ras-induced differentiation differs from its role in ras-induced mitogenesis and transformation .

PMID: 2108319 (Cell)   Terms: , rat, mouse mammary tumor, mouse
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0		Oncogene N-ras mediates selective inhibition of c-fos induction by nerve growth factor and basic fibroblast growth factor in a PC12 cell line .
1		A cell line was generated from U7 cells ( a subline of PC12 rat pheochromocytoma cells ) that contains a stably integrated transforming mouse N-ras ( Lys-61 ) gene under the control of the long terminal repeat from mouse mammary tumor virus .
2		Such cells , designated UR61 , undergo neuronal differentiation upon exposure to nanomolar concentrations of dexamethasone , as a consequence of expression of the activated N-ras gene ( I Guerrero , A Pellicer , and DE Burstein , Biochem , Biophys Res Commun 150 : 1185-1192 , 1988 ) .
3		Exposure of UR61 cells to either nerve growth factor ( NGF ) or basic fibroblast growth factor ( bFGF ) results in a marked induction of c-fos RNA , with kinetics paralleling those of NGF - or bFGF -induced expression of c-fos RNA in PC12 cells .
4		Dexamethasone-induced expression of activated N-ras p21 results in blocking of c-fos RNA induction by NGF or bFGF in a time -dependent manner .
5		Activated N-ras p21-mediated inhibition of c-fos RNA induction in UR61 cells is selective for NGF and bFGF and is not due to selective degradation of c-fos RNA .
6		Normal and transforming N-ras can trans activate the chloramphenicol acetyltransferase gene linked to mouse c-fos regulatory sequences when transient expression assays are performed .
7		Our observations suggest that N-ras p21 selectively interacts with pathways involved in induction of c-fos expression which initiate at the receptors for NGF and bFGF .

PMID: 2666584 (Cell)   Terms:
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0		Oncogene expression and cytotoxic activity of tumor necrosis factor against human cancer cells .
1		We studied the effect of recombinant tumor necrosis factor ( TNF ) on selected leukemic and breast cancer cell lines .
2		Based on their sensitivity to TNF in the presence or absence of cycloheximide ( CHX ) , these cell lines could be categorized into three phenotypes : SS , cells that are spontaneously sensitive to TNF ; RS , cells that are normally resistant to TNF but are killed in the presence of CHX ; and RR , cells that are resistant to TNF irrespective of the presence of CHX .
3		The effect of TNF on expression of c-myc , N-ras , and Ha-ras oncogenes was also studied in these cell lines .
4		Transient , minimal suppression of c-myc was observed in one cell line ( Raji ) , and an inconsistent stimulation of c-myc in another ( MCF-7OCI ) .
5	✓ Μ	No correlation was observed between the effect on oncogene expression and TNF sensitivity .

PMID: 2467732 (Patient)   Terms: case, control
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0		Expression of ras oncogene p21 protein in relation to regional spread of human breast carcinomas .
1		The oncogenes most frequently detected in human tumors belong to the ras gene family ( Ha-ras , Ki-ras , and N-ras ) .
2		These genes encode a group of closely related 21,000 dalton proteins termed p21 .
3		An immunohistochemical study of ras p21 expression was carried out on paraffin sections of 54 human breast carcinomas using monoclonal antibodies to p21 .
4		The control group consisted of ten cases of benign fibrocystic disease .
5		The p21 expression was significantly higher in cancer cells than in epithelial cells of control specimens .
6	Μ	No correlations , however , were observed between oncogene product expression and tumor size , histologic type , or grade .
7		As a group , tumors with axillary lymph node metastases expressed higher levels of ras p21 than nonmetastasizing tumors .
8		However , because of the significant overlap in individual p21 values , it is unlikely that the immunohistochemical assay for p21 could be used to predict the behavior of mammary carcinomas .

PMID: 2564734 (Patient)   Terms:
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0		Oncogenes and human breast cancer .
1		The role of oncogenes in breast tumorigenesis is unclear .
2	Μ	Alterations and/or amplification of several oncogene sequences have been observed in primary human breast tumors , in breast tumor cell lines , and in mammary tumors in model systems .
3		In principle , such alterations could be sites of primary lesions for human breast cancer , causes of tumor progression or metastasis , or simply secondary lesions of highly aberrant tumor genomes .
4		The present study tested genetic linkage of breast cancer susceptibility to nine oncogenes in 12 extended families including 87 affected individuals .
5		Lod scores for close linkage of each candidate sequence to breast cancer were -19.6 for HRAS , -12.3 for KRAS2 , -1.0 for NRAS , -6.0 for MYC , -6.1 for MYB , -8.2 for ERBA2 , -7.9 for INT2 , and -5.1 for RAF1 .
6		Regions of chromosome 11p associated with tumor homozygosity and the region of 3p carrying the gene for Von Hippel-Lindau disease could also be excluded from linkage to human breast cancer .
7		The 5-kb allele of the MOS oncogene , previously proposed to be associated with breast cancer , was absent in these families , suggesting that polymorphism at this locus is not associated with inherited susceptibility .
8		These results strongly suggest that oncogenes are not the sites of primary alterations leading to breast cancer .
9	✓	On the other hand , alterations in one or more of these sequences may be associated with tumor progression .	GM-ASS-RO

PMID: 2642738 (Cell)   Terms:
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0	✓	Incidence of activating ras oncogene mutations associated with primary and metastatic human breast cancer .	GM-ASS-DS
1		To test the hypothesis that ras activation is involved in the final stages of breast cancer progression , we analyzed tumor DNA derived from 60 different patients and extracted from 40 invasive primary breast tumors , seven lymph node and skin metastases , nine metastatic effusions , and five established breast cancer cell lines .
2	Μ	The polymerase chain reaction technique was used to amplify DNA fragments containing Kirsten - ( Ki - ) , Harvey - ( Ha - ) , and N-ras codons 12 , 13 , and 61 which were then probed on slot-blots with labeled synthetic oligomers to detect nonconservative single base mutations .
3	Μ	Activating mutations were found in one of 40 primary tumors ( Ki-ras codon 13 ) , zero of seven lymph node and skin metastases , one of nine metastatic effusions ( Ki-ras codon 12 ) , and two of five cell lines ( Ki-ras codons 12 and 13 ) .
4		These results indicate that activating ras mutations are rarely involved in either the initiation or metastatic progression of human breast cancer .

PMID: 2547415 (Patient)   Terms:
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0		Cellular protoonocogenes are infrequently amplified in untreated non-small cell lung cancer .
1		To examine a potential contribution of protooncogene abnormalities other than point-mutational activation of the K-ras protooncogene in the classification of non-small cell lung cancer , amplification of cellular protooncogenes was studied in 47 lung tumour specimens obtained at thoracotomy and in four lung tumour cell lines .
2		The primary tumours included 21 adenocarcinomas , nine large - cell carcinomas , 13 epidermoid carcinomas , one carcinoid and three metastases of primaries outside the lung .
3		The copy numbers per haploid genome of 11 protooncogenes in every tumour sample were determined : H-ras , K-ras , N-ras , c-myc , N-myc , L-myc , erbB , mos , myb , ncu ( erbB-2 ) and ral amplifications .
4		The c-myc gene was amplified 5-7-fold in two adenocarcinomas , the H-ras gene 3 5-fold in one adenocarcinoma , while the K-ras and the neu gene were amplified in lung metastases from a colorectal and a breast cancer primary respectively .
5	Μ	None of the tumours with an amplified protooncogene simultaneously harboured a mutationally activated K-ras gene .
6		We conclude that amplification of the investigated protooncogenes is a rare event in non-small cell lung cancer .
7	Μ	In view of the two c-myc amplifications detected , a systematic study of c-myc expression levels in non-small cell lung cancers appears worthwhile .

PMID: 3133379 (Cell)   Terms: , mouse, mouse mammary tumor
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0		Dexamethasone -dependent inhibition of differentiation of C2 myoblasts bearing steroid -inducible N-ras oncogenes .
1		ras proteins are localized to the plasma membrane where they are postulated to interact with growth factor receptors and other proximal elements in intracellular cascades triggered by growth factors .
2		The molecular events associated with terminal differentiation of certain skeletal myoblasts are inhibited by specific polypeptide growth factors and by constitutive expression of transforming ras oncogenes .
3		To determine whether the inhibitory effects of ras on myogenic differentiation were reversible and to investigate whether muscle-specific genes remained susceptible to ras -dependent repression in terminally differentiated myotubes , the murine myoblast cell line , C2 , was transfected with a plasmid containing a mutationally activated human N-ras oncogene under transcriptional control of the steroid -sensitive promoter of the mouse mammary tumor virus long terminal repeat .
4		Addition of dexamethasone to myoblasts bearing steroid -inducible ras oncogenes prevented myotube formation and induction of muscle creatine kinase and acetylcholine receptors .
5		Inhibition of differentiation by dexamethasone occurred in a dose -dependent manner and was a titratable function of ras expression .
6		In the presence of dexamethasone , myoblasts bearing steroid -inducible ras genes retained their dependence on exogenous growth factors to divide and exhibited contact inhibition of growth at confluent densities , indicating that the inhibitory effects of ras on differentiation were independent of cell proliferation .
7		Removal of dexamethasone from N-ras-transfected myoblasts led to fusion and induction of muscle-specific gene products in a manner indistinguishable from control C2 cells .
8		Examination of the effects of culture media conditioned by ras-transfected myoblasts on differentiation of normal C2 cells yielded no evidence for inhibition of differentiation via an autocrine mechanism .
9		In contrast to the ability of N-ras to prevent up-regulation of muscle-specific gene products in myoblasts , induction of N-ras in terminally differentiated myotubes failed to extinguish muscle-specific gene expression .
10		Together , these results suggest that oncogenic ras proteins reversibly activate an intracellular cascade that prevents establishment of the differentiated phenotype .
11		The inability of ras to extinguish muscle-specific gene expression in terminally differentiated myotubes also suggests that ras may interfere with an early step in the pathway of myoblasts toward the differentiated state .

PMID: 3283542 (None)   Terms:
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0		The ras gene family and human carcinogenesis .
1		It has been well established that specific alterations in members of the ras gene family , H-ras , K-ras and N-ras , can convert them into active oncogenes .
2		These alterations are either point mutations occurring in either codon 12 , 13 or 61 or , alternatively , a 5 - to 50-fold amplification of the wild-type gene .
3		Activated ras oncogenes have been found in a significant proportion of all tumors but the incidence varies considerably with the tumor type : it is relatively frequent ( 20-40% ) in colorectal cancer and acute myeloid leukemia , but absent or present only rarely in , for example , breast tumors and stomach cancer .
4		No correlation has been found , yet , between the presence of absence of an activated ras gene and the clinical or biological features of the malignancy .
5		The activation of ras oncogenes is only one step in the multistep process of tumor formation .
6		The presence of mutated ras genes in benign polyps of the colon indicates that activation can be an early event , possibly even the initiating event .
7		However , it can also occur later in the course of carcinogenesis to initiate for instance the transition of a benign polyp of the colon into a malignant carcinoma or to convert a primary melanoma into a metastatic tumor .
8		Apparently , the activation of ras genes is not an obligatory event but when it occurs it can contribute to both early and advanced stages of human carcinogenesis .

PMID: 3330785 (Patient)   Terms:
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0	✓	Alterations to either c-erbB-2 ( neu ) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis .	GM-ASS-RO
1		We have examined the genomic organisation of c-myc , N-myc , L-myc , neu and N-ras in tissue from 41 breast carcinomas , lymph node metastases from 10 of these carcinomas , one fibrosarcoma , 10 cases of benign fibrocystic breast and six fibroadenomas .
2	Μ	We have not observed an alteration in either N-myc or N-ras in any of the samples studied .
3		We have seen a 2-fold amplification of L = myc in DNA from one infiltrating ductal ( ID ) carcinoma , but otherwise we have seen no alterations to this gene .
4		Amplification of c-myc was seen in 22% of ID breast carcinoma sample .
5		Levels of amplification ranged from 2 - to 10-fold .
6	Μ	We have found a significant ( p less than 002 ) correlation between an altered c-myc gene and a very poor short-term prognosis .
7		Amplification of neu was seen in 19% of ID breast carcinomas , but the levels of amplification were higher than those seen for c-myc .
8	✓	Alterations to neu also correlated well with poor short-term prognosis ( p less than 00002 ) .	RO-ASS-GM
9	Μ	Finally , we have observed a low level of amplification of c-myc in DNA from a benign fibrocystic breast lesion .
10		This lesion exhibited some features characteristic of those thought to be associated with an increased risk of developing breast cancer .

PMID: 3770994 (Patient)   Terms:
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0		Differential expression of cellular oncogenes in benign and malignant human breast tissue .
1		We have examined 62 specimens of benign fibrocystic breast tissue , fibroadenomas , carcinomas and surrounding non-malignant tissue excised from 50 patients to determine the level of expression of 4 cellular oncogenes , c-myc , c-H-ras , c-K-ras , and c-N-ras .
2	Μ	Our results demonstrate that in breast carcinoma the frequency and relative level of expression of these oncogenes are significantly greater than those found for benign breast tissue .
3		However , some fibrocystic specimens having prominent hyperplastic features also exhibited enhanced oncogene expression .
4		In view of the association between the increased frequency of carcinoma of the breast in women with a previous history of benign breast disease , it will be interesting to follow up donors of benign specimens to see if there is any relationship between the expression of oncogenes in such lesions and the development of carcinomas .

PMID: 3023052 (None)   Terms: , mouse, mouse mammary tumor
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0		Transformation and stimulation of DNA synthesis in NIH-3T3 cells are a titratable function of normal p21N-ras expression .
1		A plasmid has been constructed which contains the normal human N-ras proto-oncogene under the transcriptional control of the steroid -sensitive promoter of the mouse mammary tumor virus long terminal repeat .
2		This plasmid has been introduced into NIH-3T3 cells producing a clone of cells , T15 , which is phenotypically normal in the absence of the transcription inducer , dexamethasone , and transformed when treated with high levels of the inducer .
3		At lower levels of dexamethasone , both morphological transformation and stimulation of DNA synthesis are titratable functions of p21N-ras levels .
4		T15 cells have been used to demonstrate that : (i) a 20 - to 50-fold over-expression of normal p21ras is required for complete cellular transformation , ( ii ) p21N-ras expression induces DNA synthesis and the effect can be amplified by epidermal growth factor , ( iii ) moderate increases in normal p21ras expression can influence cell behaviour .

PMID: 3524819 (Patient)   Terms:
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0		Loss of a c-H-ras-1 allele and aggressive human primary breast carcinomas .
1		The human H-ras protooncogene was shown to be expressed in 16 of 22 invasive ductal carcinomas of the breast .
2	Μ	The K - and N-ras protooncogenes were either not expressed or expressed at low levels .
3	Μ	No amplification or rearrangement of the three ras genes was detected among the 104 breast carcinoma DNAs tested .
4		These results indicate that the overexpression of H-ras in human breast tumors is not correlated with alteration of the protooncogene .
5	Μ	In addition , we did not find any point mutation at the codon 12 of the H-ras or K-ras protooncogenes in 32 and 64 , respectively , tumor DNAs examined .
6		However , in tumor DNAs from 14 of 51 patients , heterozygous for H-ras-1 related BamHI restriction fragments , one allele was lost .
7		This allele loss did not alter ras Mr 21,000 protein expression .
8	Μ	Correlation with clinicopathological data showed , however , that the loss of one H-ras-1 allele in breast carcinoma DNAs is significantly linked to histological Grade III tumors , the lack of estrogen and/or progesterone receptors , and the subsequent occurrence of distal metastasis .
9		Our results thus indicate that the loss of one H-ras-1 allele correlates with the most aggressive primary carcinomas of the breast .

PMID: 3082820 (Patient)   Terms: , rat, rat mammary tumor
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0		Metastatic ability and expression of c-fos oncogene in cell clones of a spontaneous rat mammary tumor .
1		It was found that cell clones c1-2 , cl-2r , c1-3 , c1-4 and c1-6 of a spontaneous rat mammary tumor , c-SST-2 , exhibit different degrees of metastatic ability : c1-2 , c1-3 , c1-6 were highly metastatic , while c1-2r and c1-4 were weakly metastatic .
2		The expression of several oncogenes in these clones was examined .
3		The amounts of myc mRNA in the clones were nearly the same .
4		Expression of N-ras mRNA was higher in c1-2r and c1-4 than in c1-2 , c1-3 and c1-6 .
5		On the other hand , the amounts of fos mRNA in the weakly metastatic clones were markedly lower than those in the highly metastatic clones .
6		These results suggest that fos oncogene plays a role in the high metastatic ability of c-SST-2 .

PMID: 3986769 (Cell)   Terms:
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0		Varying degrees of amplification of the N-ras oncogene in the human breast cancer cell line MCF-7 .
1	Μ	The oncogene N-ras has been found to be amplified ( congruent to 20 copies ) in the human breast carcinoma cell line MCF-7 .
2		The amplified sequences have been localized to a marker chromosome by in situ hybridization .
3		Sublines of MCF-7 , serially passaged in different laboratories , have marked variation in the degree of N-ras amplification .
4		The differing degrees of amplification of N-ras are further evidence of heterogeneity within MCF-7 subclones .
5		The phenomenon may not have general relevance for breast cancer , since other breast cancer cell lines and DNA from patient biopsies failed to show evidence of N-ras amplification .

PMID: 6092933 (Cell)   Terms: , mice
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0		New human transforming genes detected by a tumorigenicity assay .
1		We have developed a sensitive bioassay for transforming genes based on the tumorigenicity of cotransfected NIH3T3 cells in nude mice .
2		The assay differs substantially from the NIH3T3 focus assay .
3		Using it , we have detected the transfer of three transforming genes from the DNA of MCF-7 , a human mammary carcinoma cell line .
4		One of these is N-ras , which is amplified in MCF-7 DNA .
5		The other two , which we have called mcf2 and mcf3 , do not appear to be related to known oncogenes .
6		We cannot detect their transfer by using the NIH3T3 focus assay .
7		We do not yet know whether either mcf2 or mcf3 is associated with genetic abnormalities in MCF-7 cells .

PMID: AACR_2016-5010 (Patient)   Terms:
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0		Prediction of therapy resistance by targeted massive-parallel sequencing in primary HER2-positive breast cancer .
1		Background : Massive parallel sequencing is a promising tool to investigate key molecular events in cancer .
2		Genomic alterations , such as PIK3CA mutations , are important for response to therapy in HER2+ breast cancer ( BC ) .
3		We have investigated genomic alterations in 364 pretherapeutic core biopsies from two prospective clinical trials with or without anti-HER2 therapy .
4		Methods : A total of 417 formalin-fixed paraffin embedded samples from HER2+ tumors of the neoadjuvant GeparTrio ( G3 without anti-HER2 treatment ) and GeparSepto ( G7 with dual blockade and randomization for paclitaxel versus nab-paclitaxel ) study were analyzed by deep targeted massive parallel sequencing , which was successful in 364 tumors ( 87% ) .
5		We interrogated hot spot regions of 22 genes ( including TP53 , PIK3CA , CDH1 , FBXW7 , PTEN , AKT1 , ATM , BRAF , EGFR , ESR1 , FGFR2 , HRAS , KRAS , NRAS , SF3B1 ) with a minimum coverage of 500 .
6		Only non-synonymous mutations with allele frequencies 10% were taken into consideration .
7	Μ	Results : A total of 291 non-synonymously mutated genes were detected in the 364 tumor samples , the most commonly mutated genes were TP53 ( 47% ) , and PIK3CA ( 24% ) , respectively .
8		EGFR , KRAS , NRAS , HRAS were combined to the XRAS group with 9 ( 25% ) mutations. 151 tumors had no , 148 one , 57 two , and 8 tumors three or more mutated genes .
9		There were no statistical significant differences between HR+ and HR - HER2+ tumors ; overall 141/252 HR+ and 72/112 HR - tumors had a mutation .
10		HR+ tumors had TP53 mutations in 112/252 ( 444% ) ; PIK3CA mutations in 53/252 ( 210% ) and XRAS mutations in 5/252 ( 20% ) .
11		HR - tumors had 60/112 ( 536% ) TP53 mutations , 34/112 ( 304% ) PIK3CA mutations and 4/112 ( 36% ) xRAS mutations .
12		Response rates ( pCR , ypT0 ypN0 ) were evaluated separately for the two trials .
13	✓	In G7 the pCR rate was 64.7% in the group with a TP53 mutation versus 60.6% in the group without ( p = 0545 ) .	GM-ASS-RO
14		The pCR rate was significantly lower in the PIK3CA mutant versus wild type ( wt ) group ( 477% versus 667% ; p = 0009 ) .
15		This effect was seen in the HR+ ( 439% versus 613% ; p = 0052 ) and the HR - cohort ( 542% versus 800% ; p = 0029 ) .
16	✓	In the nab-paclitaxel cohort , pCR rates were significantly lower in patients with PIK3CA mutations compared to those without ( 387% vs. 720% ; p = 0001 ) , whereas in the paclitaxel group , there was no significant difference between patients with and without PIK3CA mutations ( 559% vs. 609% ; p = 0690 ; interaction p = 0039 ) .	GM-ASS-RO, RO-ASS-GM
17	✓	Neither TP53 nor xRAS mutations showed a significant effect on response and treatment effect .	GM-ASS-RO
18	✓	In G3 the pCR rate was 16.3% in the PIK3CA wt cohort compared to 23.7% in the mutant cohort ; p = 0.339 .	GE-ASS-RO
19	Μ	Conclusion : Targeted NGS on FFPE core biopsies reliably identified the most common genomic alterations in HER+ BC .
20	✓	PIK3CA mutation in HER2+ BC predicts resistance to anti-HER2 therapy .
21	Μ	PIK3CA mutations were found to be predictive for response to nab-paclitaxel in G7 .
22		The results show that mutational alterations are relevant for response in HER2+ BC .

PMID: ASCO_93774-114 (Patient)   Terms:
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0		Mutational analysis of circulating tumor cells in breast cancer patients by targeted clonal sequencing. .
1		Background : The molecular signature of circulating tumor cells ( CTCs ) may serve as a surrogate marker for accurate description of the metastatic tumor of interest , especially in the setting of treatment response and selection .
2	Μ	We present a method for mutational analysis of CTCs in metastatic breast cancer ( MBC ) patients by using an emulsion-formulated , semiconductor-based , targeted clonal sequencing platform .
3		Methods : CTCs in MBC patients were enriched by a microfluidic OncoCEE device using antibodies against both epithelial and mesenchymal markers .
4		Genomic DNA was extracted from enriched CTC samples .
5		Emulsion-based multiplex-PCR targeted for various cancer genes was performed , after which semiconductor-based deep sequencing was completed .
6		The read error rates were analyzed based on quality score and context of sequence including homopolymers .
7	Μ	Statistical significance for each mutational analysis was assessed using a method based on beta-binomial distribution .
8		Results : Of the 17 patients samples obtained , we were able to enrich CTC samples in 9 of them ( CTC range 1-1063 , median = 12 ) .
9		Multiplex targeted sequencing was performed on DNA from the enriched CTC patient samples ( purity range 03-6% ) .
10		Greater than 3000-fold coverage was accomplished .
11		Missense mutations at E545D on PIK3CA ( p= 20e-07 ) , F354L on STK11 ( p = 20e-04 ) , and Q61R on NRAS ( p = 20e-07 ) were detected .
12		Novel mutations of L540F and Q1033K within the hot spot regions of PIK3CA were observed ( p = 13e-04 ) .
13	Μ	Genomic DNA from WBCs from a healthy female was analyzed concurrently as a negative control , in which none of the mutations were observed .
14	Μ	Conclusions : Mutational analysis of CTCs in MBC patients can be accomplished by deep sequencing .
15	Μ	We developed a de novo protocol for clonal mutation analysis on CTCs in MBC and detected various significant and novel mutations .
16		We anticipate reporting sequencing results on CTCs and matched WBCs , as negative controls , from 40 MBC patients .
17		This will provide the foundation for the future studies in which we will compare the mutational profile between CTCs and primary/metastatic tumors .
18	Μ	We intend to validate clonal mutational analysis of CTCs as a predictive blood-based biomarker in subsequent trials .

PMID: AACR_2014-5024 (None)   Terms: clinical trial, Phase I, genetically engineered murine models, mice
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0		mDX400 , the murine analog against the anti-PD1 antibody MK-347 is active in immunocompetent , autochthonous murine models of melanoma and breast cancer .
1		Although effective therapies exist for BRAF-mutant metastatic melanomas ( MM ) and ER+/PR+/HER2+ breast cancers , fewer options are available for the more aggressive triple negative breast cancers ( TNBC ) and Ras-mutant MM .
2		Immune infiltration is frequently observed in patient subsets with MM or TNBC .
3		An anti-tumor host immune response may be restrained by the expression of immune checkpoint proteins , such as the programmed death 1 ( PD1 ) protein .
4		We evaluated mDX400 , a murine version of the anti-PD-1 antibody MK-3475 that is currently in human clinical trials , in genetically engineered murine models ( GEMMs ) of melanoma and breast cancer ( BC ) .
5		PD1 antibody was used alone and in combination .
6		Models studied were for basal-like , TNBC (C3TAg) , Claudin-Low breast cancer p53null , luminal BC (MMTV-Her2/Neu) , RAS-driven melanoma ( Tyr-H-Ras and null for Ink4a/Arf ( TRIA ) ) and BRaf-mutant , Pten-deficient melanoma ( BRaf/Pten ) .
7		Mice were housed , treated , and evaluated in the Mouse UNC Lineberger Comprehensive Cancer Center Phase I Unit ( MP1U ) .
8		mDX400 and isotype antibody ( 10mg/kg IP qw ) were supplied by Merck & Co. , Inc .
9		Murine cohorts were assessed weekly and therapeutic intervention began once tumors reached 40-64mm3 .
10		TNBC models were treated with Carboplatin ( C , 50mg/kg IP qwk ) in combination with mDX400 .
11		mDX400 was administered as a single agent in Melanoma GEMMs .
12		Endpoints were maximal response at 21 days and median overall survival ( OS ) .
13		In the C3TAg BC model , mDX400 did not exhibit single-agent activity , but substantial synergy was observed in combination with C [partial response ( PR ) or CR in 12 of 15 vs. 0 of 19 in non-treated animals , Fisher's exact p = 0.006 or vs. C alone 5 of 13 animals , p = 0.05] and prolonged OS ( 41 vs. 28 days in NT , log-rank p = 0006 or C only 28 days , p = 0006 ) in the C3TAg model .
14		Treatment with single-agent mDX400 induced a marked response in the RAS-driven TRIA melanoma model that is resistant to multiple systemic treatments .
15		mDX400-treated TRIA mice enjoyed an almost tripling of OS [median 56 vs. 21 days , p = 0006] .
16		BRaf/Pten melanomas did not respond to mDX400 .
17		Likewise mDX400 plus C provided no benefit to the p53null or MMTV-Her2/Neu BC GEMMs vs . C alone .
18		Our data show differential response of PD-1 antibody therapies to various melanoma and BC models , the latter in combination with C .
19		The responsiveness of a RAS-driven melanoma model to mDX400 is consistent with earlier reports about the clinical benefit of patients with NRAS-mutant melanoma to Ipilimumab , and the lack of PD-L1 expression and immune infiltrates of PTEN-deficient melanomas .
20		At the meeting we will report expression of PD-L1 and other immune checkpoint proteins by cancer cells .
21		The basis whereby carboplatin potentiates the activity of anti-PD1 in TNBC is an area of ongoing study .

PMID: AACR_2016-5199 (None)   Terms: in vivo, xenograft, clinical trial
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0		An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor -based therapies in melanoma .
1		Aberrant cell cycle progression is a hallmark feature of cancer cells .
2		Cyclin-dependent kinase 4 and 6 ( CDK4/6 ) drive progression through the G1 stage/NN of the cell cycle , atleast in part , by inactivating the tumor suppressor , retinoblastoma ( RB ) .
3		CDK4/6 are targetable and the selective CDK4/6 inhibitor , palbociclib ( IBRANCE/PD-0332991 ) , was recently FDA approved for the treatment of estrogen receptor -positive , HER2-negative advanced breast cancer .
4		In cutaneous melanoma , driver mutations in NRAS and BRAF signal to promote CDK4/6 activation suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit most likely in combination with BRAF and/or MEK inhibitors that are FDA-approved .
5		However , the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined .
6		Furthermore , in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking .
7		Here , we describe the heterogeneous effects of CDK4/6 inhibitors , the expression of anti-apoptotic proteins that associate with response to CDK4/6 and MEK inhibitors , and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts .
8		These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma .

PMID: AACR_2015-2161 (None)   Terms: in vitro, in vivo, xenograft, mouse, mouse xenograft, mouse xenograft models
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0		Activation of the MAPK pathway in combination with PTEN loss leads to aggressive primary tumor formation .
1		Breast cancer is the most frequent malignancy in women , and although many breast cancers are curable via surgery , approximately one quarter maintain a latent and insidious characteristic of slow growth .
2		The loss of the tumor suppressor PTEN is associated with breast cancer stage , increased lymph node status , and disease-related death , and the high rate of loss in primary tumors suggests a potential role in initiation and/or progression of the disease .
3		Additionally , a large fraction of breast tumors carry oncogenic mutations resulting in the hyper-activation of the MAPK/ERK cascade ( 20%-25% ErbB2 , 5% KRAS , 2% BRAF , 1% HRAS , 1% NRAS ) .
4		Hyperactivation of survival and growth pathways is considered a hallmark of many human carcinomas , including breast cancer .
5		The overactivation of the PI3K pathway (PTEN loss) or the MAPK pathway could grant a cell the ability to circumvent inhibitory pathways .
6		However , specific cellular alterations in human breast epithelium controlled by PTEN inactivation and/or Ras activation , which lead to early primary tumor formation , remain poorly defined .
7		Since the current view of cancer is based on a multi-hit hypothesis where human cancers display a multitude of genetic and epigenetic changes , and a number of such alterations are required for tumor development , the loss of PTEN ( activation of the PI3K pathway ) and expression of activated K-Ras ( V12 ) ( activation of the MAPK pathway ) may cooperate to promote tumorigenesis .
8		We therefore tested the hypothesis that the activation of the MAPK pathway via activated Ras expression in a PTEN-negative background promotes tumorgenicity .
9		Using the non-tumorigenic human mammary cells line , MCF-10A , we created MCF-10A PTEN-/- cells , MCF-10A KRas (V12) cells , and MCF-10A PTEN-/-KRas (V12) cells .
10	Μ	We have found that each mutation , independently and collectively , greatly enhanced cellular survival and regrowth efficiency of nutrient deprived and suspended cells in vitro .
11		Using bioluminescent mouse xenograft models , we have determined the cells with either PTEN loss or KRas (V12) expression maintain an increased persistence in vivo up to 5 weeks beyond that of the parental cells , and the combination of PTEN loss and KRas (V12) expression resulted large tumors within 4 weeks of initial injection .
12		The combination of one-hit to the PI3K pathway and one-hit to the MAPK pathways synergized to result in aggressive tumor growth , while each individual mutation only lead to cellular persistence in vivo , a characteristic that may have been previously overlooked in less sensitive xenograft models , either without bioluminescence imaging or when transplanting less genetically stable tumor cells .

PMID: AACR_2015-3096 (Patient)   Terms: in vivo, in vitro
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0		CDK4/6 as a therapeutic target in malignant melanoma .
1		Melanoma is the most deadly form of skin cancer and FDA-approved therapies such as vemurafenib and ipilimumab are associated with short-term responses and/or severe toxicities for patients .
2		Recent favorable clinical data with cyclin-dependent kinase ( CDK ) 4/6 inhibitor , palbociclib ( PD991 ) in ER+ breast cancer has rekindled an interest in targeting cell cycle progression to stop aberrant cell growth .
3		Thus , we set out to analyze the potential use of CDK4/6 inhibitors in melanoma .
4		Due to the inability of CDK4/6 inhibitors to induce apoptosis as a single agent , we explored viable combinatorial strategies that will trigger both pro-senescent and pro-apoptotic pathways that may lead to an effective treatment modality for melanoma patients .
5		Here , we demonstrate the benefit of combining a MEK inhibitor , trametinib ( GSK212 ) with PD991 both in vitro and in vivo .
6		We did not observe any enhanced effects of combining both GSK212 and PD991 in cells that are wild-type for BRAF and NRAS or an RB1-null BRAF mutant line .
7		However , B-RAF and N-RAS mutant cells exhibited an enhanced response to the combinatorial agents as compared to single agents .
8		Furthermore , we observed a dramatic increase in apoptosis in cell lines that are sensitive to combined GSK212 and PD991 treatment .
9		Expression of Inhibitor-of-Apoptosis ( IAP ) protein , survivin , was associated with response .
10		Finally , because it is important to understand how resistance develops , we have validated a novel E2F reporter system in vivo to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and possible re-activation of the pathway during acquired drug resistance .

PMID: ASCO_82277-102 (None)   Terms: prospective, retrospective, clinical trial
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0		My Cancer Genome : Web-based clinical decision support for genome -directed lung cancer treatment. .
1		Background : Lung cancer has traditionally been treated according to histologic subtype with a plateau in the efficacy of combination chemotherapy .
2	Μ	Recent advances have identified oncogenic driver mutations in lung cancer that predict response to targeted therapies .
3		However , knowledge resources are limited regarding the clinical relevance of such mutations .
4	Μ	Methods : We performed a literature review regarding the prevalence and clinical significance of various treatments for ~40 mutations in 10 genes ( EGFR , KRAS , BRAF , NRAS , PIK3CA , MEK1 , AKT1 , HER2 , PTEN , and ALK ) for non-small cell lung cancer ( NSCLC ) .
5		Data from prospective and retrospective trials as well as preclinical studies was collected .
6		Results : ~100 articles/abstracts were synthesized into the publicly available My Cancer Genome website ( mycancergenomeorg ) which launched in Jan 2011 .
7		Content includes information about the oncogene pathway ( e.g . What is EGFR - ) , the clinical significance of the gene for a specific type of cancer ( e.g . EGFR in NSCLC ) , and a summary of clinically relevant data related to a particular gene mutation ( e.g . EGFR Exon 19 deletion in NSCLC ) .
8		Information regarding mutation directed clinical trials open for accrual both at Vanderbilt Ingram Cancer Center and worldwide is provided using a direct query of clinicaltrials .
9		gov .
10		This decision support tool is integrated into Vanderbilts electronic medical record to provide actionable decision support for mutation directed treatment prioritization and clinical trial availability .
11		Clinicians , patients , and researchers with access to the internet can also access the website freely and directly .
12		Conclusions : My Cancer Genome is an international resource to assist clinicians in prioritizing genome directed cancer therapies .
13		The first implementation includes content for NSCLC .
14		We are now expanding the content to include melanoma , breast cancer , colon cancer and other malignancies .
15		New data will be incorporated on an ongoing basis .
16		We welcome public/private partnerships to expand content and make this a truly global resource .

PMID: ASCO_97602-114 (None)   Terms: clinical trial
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0		Tumor PIK3CA mutations , lymphocyte infiltration , and recurrence-free survival ( RFS ) in early breast cancer ( BC ) : Results from the FinHER trial. .
1		Background : Tumor PIK3CA mutations ( mts ) and lymphocyte infiltration ( LI ) are prognostic in BC , but their importance is unknown in HER2-positive ( HER2+ ) BC treated with adjuvant trastuzumab (T) .
2		Methods : The FinHER trial randomized 1010 patients ( pts ) with pN+ or high-risk pN- BC to 3 cycles of docetaxel (D) or vinorelbine , followed by 3 cycles of FEC .
3		Pts with HER2+ BC were further randomized to 9 weeks of T or no T ( n = 232 ) .
4		Pts treated with D and T had superior outcome in prior analyses .
5		BC samples were subjected to somatic hotspot mt profiling ( Sequenom ) and quantification of percentage tumor LI using full-face H&E sections .
6		RFS and interactions with T were explored with Kaplan-Meier and Cox regression analyses .
7		Results : The median FU time was 62 months. 935 ( 926% ) and 687 ( 681% ) tumors underwent LI and mt analysis , respectively .
8		Correlation of LI assessment between 2 pathologists was 0.78 ( p < 0001 ) .
9		54 mts detected in 13 genes were evaluated .
10		PIK3CA mts ( exons 1,2,9,13,18,20 ) was present in 25.3% ( n = 174 ) and ERBB2 mt in 4.5% ( n = 31 ) BCs .
11		Only 1 AKT mt was found and none in KRAS , BRAF , NRAS or PTEN .
12		In ER+/HER2 - , HER2+ and ER-/HER2 - subtypes the prevalence of PIK3CA mts was 30.2% , 19.5% and 9.2% ; ERBB2 mt 6.3% , 1.9% and 2.6% , respectively ( both p < 005 ) .
13		Neither PIK3CA nor ERBB2 mts were associated with RFS overall or within BC subgroups .
14		No interaction was found for the benefit with T and presence of PIK3CA mt in HER2+ BC ( interaction p = 017 T versus no T ) .
15		Increasing LI was associated with favorable RFS in ER-/HER2 - BC ( continuous score adjusted p = 0032 ) ; 3-y RFS was 90% with extensive LI ( >30% infiltrated ) versus 66% with non-extensive LI ( p = 0007 ) .
16		In HER2+ BC , whilst there was no association with prognosis overall , there was a significant interaction with the benefit from T vs.no T and increasing LI ( continuous score interaction p = 0042 ) with 3-yr RFS 96% versus 78% for extensive and non-extensive LI treated with T respectively ( p = 0014 ) .
17		Conclusions : We report 3 clinically relevant findings from this large clinical trial dataset : 1 ) PIK3CA mts were not prognostic ; 2 ) LI is a strong prognostic factor in ER-/HER2 - BC and 3 ) for the first time that extensive LI predicts benefit from adjuvant T .

PMID: AACR_2017-3031 (Cell)   Terms: in vivo, in vitro
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0		PHIP is a therapeutic target for triple negative solid tumors. .
1		Targeted therapy relies on the classification of tumors according to the major molecular drivers of the malignant phenotype , which can then help decide the therapeutic treatment .
2		However , a substantial subset of solid tumors does not express these markers , exemplified by the triple-negative subtype of breast cancer .
3		Shared molecular factors that promote the progression of these tumors , and that represent a target for their therapy , are missing .
4	Μ	We previously described a role for PHIP ( Pleckstrin Homology domain-Interacting Protein ) in the progression of melanoma , and demonstrated PHIP activation in triple-negative melanomas .
5	Μ	Analysis of the TCGA profiling efforts in melanoma , breast and lung cancer revealed PHIP expression to be enriched in triple-negative breast cancer and in the bronchiad subtype of triple-negative lung cancer .
6		Here we show the broad-based role of PHIP in the progression of triple-negative subtypes of three solid tumors ( breast and lung cancer , and melanoma ) defined by different mutational drivers and targeted therapies .
7		By using a shRNA-based targeting of PHIP in in vitro and in vivo models , we have suppressed the malignant phenotype of triple-negative MDA-MB-231 and MDA-MB-436 human breast carcinoma cells .
8		In addition , PHIP knockdown resulted in significant anti tumor effects in H1703 and Calu3 human lung cancer cells lacking mutations in EGFR , KRAS , and ALK , and in two short-term triple wild type melanoma cultures lacking mutations in BRAF , NRAS , and NF1 .
9		Suppression of PHIP expression resulted in inhibition of both tumor cell proliferation by cell survival and colony formation assays and invasion into matrigel in each of the tumor models examined , and was accompanied by suppression of pAKT , CCND1 , TLN1 , and ITGβ1 expression when assessed by western-blot or quantitative immunofluorescence .
10		The PHIP protein contains two bromodomains that can be therapeutically targeted by small molecules .
11		However , the functional activity of the PHIP bromodomains has been poorly characterized .
12		We show that PHIP co-localizes with and binds to the acetylated histone modification H4K91ac , and that both are coordinately regulated upon growth factor stimulation suggesting a new function for PHIP as a chromatin remodeler .
13		To conclude , our results identify a novel role for PHIP in the progression of solid tumors lacking the major molecular drivers , and suggest PHIP as a druggable target for the therapy of these malignancies .

PMID: ASCO_111069-132 (None)   Terms: phase I study, NCT01394016, Clinical trial
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0		A first-in-human phase I study of the CDK4/6 inhibitor , LY2835219 , for patients with advanced cancer. .
1		Background : Cyclin dependent kinases 4 and 6 ( CDK4/6 ) act with D-type cyclins to inactivate the retinoblastoma ( Rb ) tumor suppressor protein and enable cell cycle progression from G1 to S phase .
2		LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain .
3		We performed a phase 1 study to evaluate safety , pharmacokinetics , pharmacodynamics , and antitumor activity of LY2835219 .
4		Methods : 3+3 dose escalation was followed by expansions in 5 tumor types ( brain metastases permitted ) : non-small cell lung cancer ( NSCLC ) , glioblastoma , breast cancer , melanoma , and colorectal cancer .
5		LY2835219 was taken orally every 12 or 24 hours ( in escalation ) and every 12 hours ( in expansions ) on days 1-28 of a 28-day cycle .
6		Results : 55 patients ( pts ) received LY2835219 .
7		In escalation , 33 pts received LY2835219 on 1 of 2 schedules : 50 , 100 , 150 , 225 mg every 24 hours ( Q24H ) or 75 , 100 , 150 , 200 , 275 mg every 12 hours ( Q12H ) .
8		On the Q24H schedule , the maximum tolerated dose ( MTD ) was not identified .
9		On the Q12H schedule , the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg ( 1/6 evaluable pts ) and 275 mg ( 2/3 evaluable pts ) .
10		At 200mg Q12H , the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml , respectively .
11		In skin , LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase II expression .
12		In the ongoing expansions , 22 pts have received LY2835219 .
13		Across the study , the most common related adverse events were diarrhea ( 52% , including 5% G3 ) , nausea ( 30% , 4% G3 ) , fatigue ( 21% , 7% G3 ) , vomiting ( 18% , 2% G3 ) , and neutropenia ( 16% , 7% G3 ) .
14		15 pts have reached 4 cycles for stable disease or better with 3 pts achieving 8 , 16 , and 26 cycles .
15		One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles .
16		One pt with KRAS mutant NSCLC had a 27% decrease by RECIST .
17	✓	One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response .	GM-ASS-RO
18		Early clinical activity has been observed in ovarian cancer , NSCLC , breast cancer , and melanoma .
19		Conclusions : LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer .
20		Clinical trial information : NCT01394016 .

PMID: ASCO_133789-144 (None)   Terms: phase I study, NCT01237236, Clinical trial
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0		A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. .
1		Background : LEE011 , an orally bioavailable , highly specific CDK4/6 inhibitor , causes cell cycle arrest and tumor growth inhibition in multiple preclinical models with intact retinoblastoma protein ( pRb+ ) .
2		Methods : Pts withpRb+ advanced solid tumors and lymphomas were treated with escalating doses of LEE011 on a 21-of-28-d or continuous schedule .
3		Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle .
4		Primary objective : to establish the MTD and/or RP2D of LEE011 .
5		Secondary objectives : safety , efficacy , PK , and PD .
6		Results : As of Jan 17 , 2014 , 132 pts were treated ; 85 during escalation ( 501200 mg/d ) and 47 during RP2D expansion .
7		The following results are from dose escalation ( data cut-off : July 2 , 2013 ) .
8		Ten DLTs were observed in 10 pts : neutropenia ( 3 pts ) ; asymptomatic thrombocytopenia ( 2 pts ) ; mucositis , pulmonary embolism , hyponatremia , QTcF prolongation ( >500 ms ) , and increased creatinine ( 1 pt each ) .
9		The MTD and RP2D were declared as 900 and 600 mg/d on 21-of-28-d schedules , respectively .
10		The most common study drug -related AEs ( all grades ) were neutropenia ( 40% ) , leukopenia ( 36% ) , nausea ( 35% ) , and fatigue ( 27% ) .
11		G3/4 AEs included neutropenia ( 19% ) , lymphopenia ( 14% ) , and leukopenia ( 12% ) .
12		Asymptomatic QTcF prolongation ( >450 ms ) was seen at doses 600 mg/d : in 10% of pts at 600 mg/d and in 27% of pts at doses >600 mg/d .
13		Plasma exposure increases were slightly higher than dose proportional ; mean T1/2 at RP2D was 36.2 h .
14		Paired skin biopsies from 40 pts showed reductions of 50% from baseline in Ki67 and phospho-pRb in 55% and 42% of samples , respectively .
15		Among 70 evaluable pts , 2 ( 29% ; 600 mg/d ) had confirmed PRs : 1 pt with PIK3CA-mut , CCND1-amp , ER+ breast cancer ; 1 pt with BRAF/NRAS-WT , CCND1-amp melanoma .
16		SD for 4 and 6 cycles was seen in 26% and 14% of pts , respectively .
17		Conclusions : LEE011 showed an acceptable safety profile , dose dependent plasma exposure , evidence of target inhibition and preliminary signs of clinical activity .
18		The study expansion is confirming safety and efficacy .
19		Further studies are investigating LEE011 as a single agent ( neuroblastoma and malignant rhabdoid tumors ) and in combination with other agents ( breast cancer and melanoma ) .
20		Clinical trial information : NCT01237236 .

PMID: AACR_2014-4275 (Patient)   Terms: clinical trial
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0		Identifying cancer driver mutations in clinical sequencing data .
1		BackgroundCancer therapy is challenged by diverse molecular implementations of oncogenic processes and by variations in therapeutic responses .
2		So far , whole genome sequencing ( WGS ) and whole exome sequencing ( WES ) has been implemented in both research and clinical settings to identify oncogenic events in cancer genomes .
3	Μ	However , a large number of passenger mutations have been identified and true driver mutations have been disguised .
4		Distinguishing driver events from passenger events will be a key challenge for the realization of targeted therapy .
5		To elucidate driver mutations that are clinically actionable , the Institute for Personalized Cancer Therapy at MD Anderson cancer center has developed a NGS clinical sequencing platform , T200 , to sequence 202 cancer-related genes at high depth in thousands of cancer patients at MD Anderson .
6		Materials and MethodsThe T200 mutation data , including single nucleotide variants ( SNV , variant allele frequency > = 1% ) and copy number variations ( CNV ) , of more than 500 cancer patients treated in MD Anderson Cancer Center were utilized in our study .
7		Results1 .
8		By analyzing the SNV data , we identified several sets of co-occurring genes across all cancers .
9		Some sets such as KRAS/APC/SMAD4 contain driver genes from multiple signaling pathways , which may indicate essential mechanisms for tumor development and nominate targets for combinational therapy.2 .
10		We elucidated mutual-exclusive mutations that were from genes in the same or different pathways .
11		Several sets of well-known mutual-exclusive SNVs were verified in our analysis such as BRAF/NRAS SNVs in melanoma .
12		We also illustrated novel sets of mutual-exclusive mutational events , such as IDH1/PTEN/PPP1R3A SNVs in brain tumors and EGFR/FGFR3/GNAS/NOTCH4 CNVs in all cancers.3 .
13		SNVs of more than 10 genes were enriched in specific cancer types , such as IDH1 and NF1 in brain tumor , BRAF and MITF in melanoma .
14	Μ	CNVs of more than 50 genes were found enriched in one cancer type , such as PDGFRA amplifications in brain tumors and IL6R amplifications in breast cancer .
15	Μ	We observed not only expected cancer specific mutations such as BRAF SNVs but also novel mutations such as NF1 SNVs and PDGFRA amplifications.4 .
16		We performed mutual-exclusivity and cancer type enrichment analysis on SNV hotspots .
17		More than 20 SNV hotspots were elucidated , such as BRAF (V600E) in melanoma , IDH1 (R132H) in brain tumors , KRAS (G12D) in colorectal cancer , and PIK3CA (H1047L) in breast cancer .
18		In addition , multiple SNV hotspots were found to occur mutual-exclusively , such as BRAF ( V600E )/IDH1 ( R132H )/MPL (L532V) in brain tumors .
19		ConclusionDeep target sequencing enables us to systematically determine the potential driver mutation events ( including low allele frequency SNVs ) , which not only help us characterize the landscape of cancer genomic alterations , but also provide comprehensive patient molecular profile to facilitate clinical decision-making and novel clinical trial design .

PMID: AACR_2013-2897 (Cell)   Terms:
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0	✓	Discovery and characterization of driver MAPK and PI3K pathway mutations in tumors and association with drug response in cell lines. .	GM-ASS-RO
1	Μ	The MAPK and PI3K pathways are frequently altered in human cancer and are targeted by dozens of agents in clinical trials .
2		The successful application of these therapies , alone or in combination , may depend on the activation status of both pathways .
3		Next-generation sequencing of cancer exomes provides a unique opportunity to systematically survey pathway alterations in cancer .
4		Using somatic mutation data obtained from The Cancer Genome Atlas , we sought to catalog the members of the MAPK and PI3K pathways with driver mutations , the frequency of occurrence in common cancers and the frequency of co-occurrence .
5		Furthermore , we sought to characterize the association of pathway mutation status with drug response in pre-clinical models .
6	Μ	While the MAPK and PI3K pathways were frequently altered , the frequency of single and dual pathway alteration and the altered genes varied substantially across cancer types .
7	Μ	The MAPK pathway was most frequently altered in rectal ( 62% ) , colon ( 59% ) , uterine ( 31% ) and lung adenocarcinoma ( 45% ) but infrequently altered in and breast cancer ( 4% ) .
8		KRAS , BRAF and NRAS hotspot mutations were the most common pathway drivers , along with NF1 deleterious mutations in certain cancer types .
9	Μ	The PI3K pathway was most frequently altered in uterine ( 84% ) , breast ( 40% ) and glioblastoma ( 41% ) but was rarely altered in lung adenocarcinoma ( 9% ) .
10		Hotspot mutations in PIK3CA and hotspot and deleterious mutations in PTEN were the most common pathway alterations .
11	Μ	In addition , predicted driver mutations occurred in PIK3R1 , PIK3R3 , MTOR , AKT1 and AKT3 .
12	Μ	Notably , MAPK and PI3K pathway alterations co-occurred in uterine ( 30% ) , colon ( 17% ) and gastric ( 12% ) cancers more so than would be expected by chance ( p < 002 ) .
13		In contrast , other cancer types favored one pathway almost exclusively and thus had little co-occurrence .
14		For example , breast cancer significantly favored PI3K pathway whereas lung adenocarcinoma favored MAPK pathway .
15		To assess the effect of pathway mutation status on treatment response , we integrated hybrid -capture sequencing data from the Cancer Cell Line Encyclopedia with pharmacological data from over 150 compounds .
16	Μ	We found that MAPK and PI3K pathway mutations most significantly associated with sensitivity to MEK and PI3K/AKT/mTOR inhibitors , respectively .
17		Notably though , cell lines with co-occurring MAPK pathway and PIK3CA mutations were insensitive to MEK inhibitors and cell lines with co-occurring PI3K pathway and KRAS mutations were insensitive to PI3K inhibitors .
18	✓	Also , not all pathway mutations conferred equal sensitivity .
19		For example , BRAF mutants were generally sensitive , KRAS mutants were mixed and NF1 mutants were generally insensitive to MEK inhibitors .
20		Taken together , our work highlights the need to consider pathways and co-occurrence in the development of targeted therapies .

PMID: AACR_2015-4478 (Cell)   Terms: in vitro, in vivo, xenograft, mice
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0		6-Phosphofructo-2-Kinase ( PFKFB3 ) : At the crossroads of resistance to targeted cancer therapies .
1		Targeted cancer therapies that block the growth and spread of cancer by interfering with specific onco - proteins are limited by signaling mechanisms that drive intrinsic and acquired resistance .
2		In particular , the MAPK and the PI3K/AKT pathways have been found to both reduce response rates to these agents and to mediate the acquisition of resistance via mutations that activate both pathways .
3		For example , two recently approved BRAFV600E inhibitors , vemurafenib and dabrafenib , cause dramatic clinical responses in 50% of BRAFV600E + melanoma patients but universally become ineffective within 5-6 months as a result of genetic alterations that activate the MAPK and PI3K-AKT pathways , including amplifications in BRAFV600E , loss of PTEN , and activating mutations in NRAS and KRAS , MEK , AKT1/3 , PIK3CA and PIK3CG .
4		Several of these mutated signaling proteins stimulate glucose metabolism , required for survival and proliferation , in part by increasing the expression and activity of 6-phosphofructo-2-kinase ( PFKFB3 ) .
5		For example , PFKFB3 transcription is induced by HIF-1 ( which is increased by BRAFV600E , RAS and MEK ) , loss of PTEN , and PFKFB3 activity is stimulated by AKT via phosphorylation of serine 461 .
6		We postulated that PFKFB3 is an essential downstream target of targeted cancer therapies and that the multitude of mutations and amplifications in signaling pathways that cause resistance to these agents activate PFKFB3 .
7		In new studies , we demonstrate that BRAFV600E , estradiol and epidermal growth factor each regulate PFKFB3 expression in melanoma cells , breast cancer cells and NSCLC cells , respectively .
8		Moreover , we find that simultaneous inhibition of these oncoproteins or their co-ligands ( i.e. the estrogen and EGF receptors ) and PFKFB3 using a novel PFKFB3 inhibitor currently in a phase 1 trial , PFK-158 , causes a synergistic increase in apoptosis and cytotoxicity in vitro , suggesting that PFK-158 can overcome the intrinsic resistance to these agents .
9		We then decided to determine if these significant synergies would translate in vivo by investigating them in the A375 and A2058 melanoma preclinical models , and in the MCF-7 ER -dependent breast model .
10		For instance , we compared the anti-tumor effects in A375 melanoma xenograft-bearing mice of : (i) the BRAFV600E inhibitor vemurafenib ; ( ii ) PFK-158 ; or ( iii ) the combination of vemurafenib and PFK-158 .
11		Although we observed significant tumor growth inhibition with both monotherapies ( >80% ) , we only observed tumor regression with the combination therapy ( >50% ) .
12		Results in these different models will be presented .
13		Taken together , these data demonstrate that the PFKFB3 inhibitor PFK-158 may be able to universally overcome resistance to targeted cancer therapies .
14		Furthermore , we predict that phase 1/2 trials of PFK-158 in combination with targeted cancer agents will yield improvements in objective response rates as well as improvements in progression-free survival .

PMID: ASCO_116665-132 (Patient)   Terms: prospective, clinical trial, phase I trial, NCT01566019, Clinical trial
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0		Molecular screening for cancer treatment optimization ( MOSCATO 01 ) : A prospective molecular triage trialInterim results. .
1		Background : Characterization of the genomic alterations ( GA ) that could drive tumor growth of an individual patient ( pt ) is now critical to better select targeted therapies in phase I trials .
2		Methods : Pts with advanced solid tumors , who failed atleast one line of standard therapy , were offered an on-purpose tumor biopsy for molecular characterization .
3		Biopsies were mainly obtained using 18G needles under CT or ultra-sound control , from metastatic or primary tumor sites .
4		DNA extracted from fresh tumor biopsies was analyzed by CGH ( Agilent platform ) ( if 50% tumor cells in the sample ) and by sequencing for 30 target genes ( if 30% tumor cells in the sample ) .
5		An expert panel of scientists and clinicians reviewed results to determine the biological signification of the GA and match such pts to the most relevant targeted therapy available ( mainly in early clinical trials ) .
6		PFS using therapy based on GA was compared to the PFS for the most recent therapy on which the pt had just experienced progression ( PFS ratio ) .
7		Results : From December 2011 to august 2012 , 129 heavily pretreated pts ( median of 3 previous lines ) were consented .
8		Among them , 111 ( 86% ) had a dedicated tumor biopsy .
9		An actionable target was identified in 52 patients ( 40% ) .
10		Among them , 25 pts ( 23% of biopsied pts ) have been treated with a targeted therapy .
11		The median time between biopsy and molecular results was 21 days [17 28] .
12		GA of interest encompassed FGF ligand or receptor amplification ( n = 9 ) , cyclin amplification or deletion ( n = 4 ) , KRAS/BRAF/NRAS mutation ( n = 3 ) , PI3K amplification or PTEN deletion ( n = 3 ) , EGFR amplification or mutation ( n = 3 ) ( outside lung cancer ) , HER2 amplification ( n = 2 ) ( outside breast cancer ) , EML4/ALK translocation ( n = 1 ) .
13		Among the 25 pts treated according to their GA , we observed 5 PR ( 20% ) , 14 SD ( 56% ) and 3 PD ( 12% ) .
14		Three pts ( 12% ) were not evaluable because of early discontinuation of the therapy .
15		PFS ratio was >1.3 among 9 out of 19 evaluable pt ( 47% ) .
16		Conclusions : High throughput molecular analysis is feasible in daily practice .
17		It allows enrichment of phase I trials with specific GA , and leads to promising anti-tumor activity ( 20% PR as compared to the classical 7-10% PR obtained in all comers phase I trials ) .
18		Clinical trial information : NCT01566019 .

PMID: ASCO_183810-199 (None)   Terms: phase II, phase II study
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0		A phase II , open label study of tucatinib ( ONT-380 ) combined with trastuzumab in patients with HER2+ metastatic colorectal cancer ( mCRC ) (MOUNTAINEER) . .
1	Μ	Background : To improve survival for patients with mCRC , efforts are needed to identify and treat actionable genomic alterations .
2		HER2 is amplified in approximately 5-8% of patients with KRAS and NRAS (RAS) wild-type mCRC .
3		HER2 functions as an oncogenic driver and a mediator of EGFR antibody ( Ab ) resistance .
4		Although prior studies have shown that anti-HER2 therapies are active in patients with HER2+ ( HER2 IHC 3+ or HER2 amplified ) mCRC , there are no HER2 -directed therapies approved for these patients .
5		Tucatinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of HER2 , currently being developed to treat metastatic breast cancer .
6		In HER2+ CRC patient derived xenograft models , tucatinib has substantial anti-tumor activity .
7		The addition of the anti-HER2 monoclonal Ab trastuzumab augments tumor growth inhibition .
8		Methods : This single-arm phase II study will test the combination of tucatinib and trastuzumab in patients with HER2+ mCRC .
9		Eligible patients include those with RAS wild-type mCRC who have been previously treated with 5-FU , oxaliplatin , irinotecan , and an anti-VEGF monoclonal Ab .
10		Patients must have HER2+ disease by IHC , FISH , or NGS .
11		Prior treatment with anti-HER2 targeting therapy is excluded .
12		The primary objective is to assess the objective response rate for the combination .
13		Secondary objectives are to evaluate the efficacy ( PFS , OS , clinical benefit rate ) , safety , and tolerability of the combination .
14		Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored .
15		Blood will be collected at baseline and each restaging to determine if the combination eliminates HER2 amplified circulating tumor DNA .
16		Subjects will receive tucatinib at a dose of 300mg by mouth daily , and trastuzumab will be administered every 3 weeks ( 8 mg/kg IV day 1 of cycle 1 , then 6 mg/kg IV Q3 weeks ) .
17		Response will be assessed every 3 cycles ( 9 weeks ) per RECIST version 1.1 .
18		Both agents will be provided by the study .
19		This study was initiated in February 2017 .
20		Recruitment is ongoing at 8 sites in the Academic and Community Cancer Research United ( ACCRU ) network .

PMID: ASCO_152287-156 (Patient)   Terms:
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0		Mutation yield of a 34 - gene next-generation sequencing test in community-based tumor samples. .
1		Background : Several targeted therapies have been approved for treatment of solid tumors .
2		Identification of gene mutations associated with response to these targeted therapies is rapidly progressing .
3		We developed and validated a 34 - gene next-generation sequencing ( NGS ) panel and used this to test community-based samples sent for routine molecular testing for actionable gene mutations .
4	Μ	Methods : A laboratory-developed NGS test on an Ion Torrent PGM sequencer was used to determine mutation profiles for 121 consecutive , de-identified FFPE tissue samples collected from patients diagnosed with melanoma ( n = 31 ) , lung ( n = 27 ) , colorectal ( n = 33 ) , and breast cancer ( n = 30 ) .
5		NGS results were compared to those of the routine single - gene molecular tests .
6	Μ	Results : Twenty-four ( 20% ) samples had mutations detected by the originally requested tests , all of which were also detected by NGS .
7	Μ	However , NGS detected atleast 1 additional mutation not detected by the original test in 92 ( 76% ) of the 121 samples .
8	Μ	Of the additional mutations detected , 16 were actionable according to NCCN guidelines ( 3 BRAF [2 V600E and K483Q] in melanoma specimens ; 2 KRAS [A146T and L19F] , 2 BRAF [2 V600E] and 1 NRAS [Q61K] in colorectal cancer ; and 2 EGFR [E746-A750 and R680Q] and 6 KRAS [A146T , G12C , G12V , Q22K , G12A and G13C] in lung cancer ) .
9	Μ	Most of the additional mutations detected by NGS were in regions not covered by the routine molecular tests ; in the other cases , NGS may have provided greater sensitivity than the routine test .
10	Μ	Overall , mutations were detected in 21 of the 34 genes included in the NGS panel , 17 of which were detected in multiple tumor types .
11	Μ	The most frequently mutated gene was TP53 ( 64/121 ) , but 83% ( 100/121 ) of the specimens harbored mutations in atleast 1 gene other than TP53 .
12	Μ	Conclusions : This NGS assay frequently detected actionable mutations not identified by routine single - gene tests .
13		These findings suggest that broader mutation profiling of solid tumors , as with the 34 - gene NGS mutation panel , could provide additional information for treatment selection in a substantial proportion of cases .

PMID: AACR_2014-915 (Patient)   Terms: phase I
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0		Expanded biomarker results from a phase I dose escalation study of GDC-0032 , a beta isoform-sparing PI3K inhibitor .
1		The phosphoinositol-3-kinase ( PI3K ) signaling pathway is one of the most frequently activated pathways in oncogenesis , and controls critical cellular processes such as proliferation , transcription and survival .
2		GDC 0032 is an orally bioavailable , potent , and selective inhibitor of Class I PI3K alpha , delta , and gamma isoforms , with 30 fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform .
3	Μ	The gene that encodes the p110 alpha isoform of PI3K , PIK3CA , is frequently mutated in breast , colorectal and endometrial cancers .
4		Preclinical data indicate that GDC-0032 has increased activity against PIK3CA mutant cancer cell lines .
5		As presented by Juric et al. , 34 patients were enrolled in this study and dose escalation has been completed ( Juric D et al AACR 2013 , Abstract LB-64 ) .
6		Metabolic partial responses via FDG-PET were observed in 6 out of 13 patients assessed , and clinical partial responses ( PRs ) were observed in 6 patients , with 5 of these patients having PIK3CA mutant cancers .
7		Tumor tissue was obtained from 30 out of 34 patients enrolled onto the study .
8		The most frequently recruited cancer type was breast cancer ( 41% ) followed by colorectal ( 15% ) and lung cancer ( 15% ) .
9		Fourteen patients enrolled onto the study had PIK3CA mutant tumors ( 41% ) as determined using a TaqMan-based PCR assay .
10		Three patients had total loss of PTEN expression , as assessed by immunohistochemical staining , and a further 3 patients had reduced PTEN expression based on a H-score assessment .
11		Out of the 6 patients that had reduced PTEN expression , 2 patients had coexisting mutations with PIK3CA .
12	Μ	Where known , 4 out of 5 patients that had a PR showed intact PTEN expression , with the fifth patient having reduced PTEN expression .
13	Μ	Samples were further analyzed using an in-house developed PCR-based multiplexed assay that detects activating mutations within an additional ten oncogenes .
14		PIK3CA mutations were largely mutually exclusive with mutations in the Ras pathway , however 3 out of the 14 PIK3CA mutant patients had a coexisting mutation within KRas .
15		A further 2 patients had KRas mutations , 1 patient had a NRas mutation and 2 patients had EGFR mutations .
16		Preliminary analysis suggests lack of benefit in patients with KRas mutations treated with GDC-0032 single agent .
17		Optional on-study biopsies were collected from 2 patients and demonstrated pharmacodynamic inhibition of the PI3K pathway as assessed by reverse phase protein array for approximately 45 endpoints , including 1 patient at the lowest dose .
18		In conclusion , our preliminary data indicates that GDC-0032 demonstrates single agent activity in patients with PIK3CA mutations tumors with unaltered PTEN or MAP-kinase pathways .

PMID: ASCO_184601-199 (Patient)   Terms:
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0		Characterization of tumor mutation load ( TML ) in solid tumors. .
1		Background : Rapid advances in immunotherapy have created a need for biomarkers to improve patient treatment selection .
2		TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity .
3		Methods : TML was assessed in 8020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592 - gene panel .
4		High TML was set at 17 mutations per megabase ( mt/MB ) based on an established concordance ( > 99% ) with MSI-High in colorectal cancer ( CRC ) .
5		Results : Mean TML was highest in melanoma ( Mel ; 21 mt/MB ) , NSCLC (11 mt/MB) , and bladder cancer ( BLC ; 11 mt/MB ) , whereas prostate cancer ( PC ) , pancreas adenocarcinoma ( PA ) , and renal cell carcinoma ( RCC ) had the lowest levels ( all 6 mt/MB ) .
6	Μ	High TML was seen most frequently in Mel ( 36% ) , NSCLC ( 15% ) , BLC ( 15% ) , and anal cancer ( SCCA ; 9% ) ; and least frequently in PA ( 16% ) and RCC ( 05% ) .
7		Primary NSCLC carried lower TML than its brain metastases ( 11 vs. 16 mt/MB , p < 0001 ) .
8		Older age was associated with higher TML in Mel ( p = 0001 ) , CRC ( p = 0009 ) , breast cancer ( BC ; p = 001 ) , and NSCLC ( p = 002 ) .
9		Higher TML was seen in males than in females for Mel ( p = 0002 ) and NSCLC ( p < 0001 ) .
10		Presence of mutations in oncogenic driver genes such as EGFR , ALK , ROS1 RET fusions , cMET exon 14 skipping correlated with lower TML in NSCLC ( 69 vs. 12 mt/MB , p < 0001 ) , as did BRAF and NRAS mutations in Mel ( 17 vs. 26 , p = 0003 ) .
11		Conversely , mutations in tumor suppressor genes such as ARID1A ( CRC , NSCLC , and BLC ) and NF1 ( BC , CRC , Mel , BLC , and NSCLC ) were associated with higher TML ( p < 005 ) .
12		MSI-high was correlated with high TML in CRC and gastric cancers ( p < 005 ) .
13		Conclusions : TML varied significantly among different cancers .
14		High TML was associated with older age , absence of oncogenic mutations and presence of tumor suppressor gene mutations .
15		Future studies will assess the impact of TML on clinical outcome and establish its role in selecting patients for immunotherapy .

PMID: AACR_2015-2990 (Patient)   Terms:
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0		Evidence for diverse mechanisms of tumorigenesis in breast and ovarian tumors of BRCA1/2 carriers .
1		Germline mutations in the tumor suppressors BRCA1 and BRCA2 lead to increased risks of breast and ovarian cancers atleast in part due to their roles in homologous recombination based double stranded DNA repair .
2		Genetic alterations including loss of the wild-type BRCA1/2 allele , PTEN loss and TP53 mutations are thought to contribute to genomic instability in susceptible tissues and therefore tumor formation .
3		In order to further investigate the mechanisms of tumorigenesis in BRCA1/2 carriers , we performed whole exome sequencing of 39 breast and ovarian tumors and matched blood germline DNA .
4	Μ	Sequencing data were analyzed using GATK and MuTECT for variant calls and ngCGH and Sequenza for copy number analysis .
5	Μ	Using cellularity corrected tumor versus germline allele frequency calculations , we found no evidence of loss of heterozygosity ( LOH ) in 17% of BRCA1 tumors ( n = 4 of 24 ) and 40% of BRCA2 tumors ( n = 6 of 15 ) .
6		Genomic instability as measured by percentage of genome in the diploid state showed that BRCA1/2 tumors with no evidence of LOH had decreased genomic instability ( average% genome diploid 76+27% versus 57+16% , p = 001 ) with no difference in the overall somatic mutation rate ( average 50+71 versus 83+156 single nucleotide variants per megabase , p = NS ) .
7		While there were also no significant differences in the average number of predicted deleterious somatic mutations in BRCA1/2 tumors with no LOH versus tumors with LOH ( n = 13+15 versus 13+6 , p = NS ) , tumors without LOH were significantly less likely to have mutations or loss in TP53 or loss of PTEN ( 50% versus 93% , p = 0007 ) .
8		Of the ten tumors with no LOH , five were from patients who had received prior cytotoxic chemotherapy .
9		Other tumors with no LOH were from patients with atypical presentations including a mixed histology epithelial ovarian tumor in a BRCA1 carrier , and a triple negative breast cancer in a 70 year old BRCA2 carrier .
10		Of the 29 tumors with evidence of LOH , no patient had received cytotoxic chemotherapy for a prior malignancy or in the neoadjuvant setting .
11	Μ	No recurrent driver mutations other than TP53 mutations were identified in the BRCA1/2 tumors with or without LOH .
12	Μ	Twenty-six pathogenic likely driver mutations were identified in 25 cancer genes outside of TP53 , including NRAS , PIK3CA , and ABL2 .
13		Our results indicate that approximately 75% of tumors in BRCA1/2 germline mutation carriers arise via a classic pathway involving LOH of the wildtype allele , loss of function of TP53 and/or PTEN and significant genomic instability .
14		However , approximately 25% of tumors may arise via an alternative pathway , possibly related to prior chemotherapy in some cases .
15		Further studies are needed to determine the molecular and clinical factors associated with this proposed classic versus atypical pathway of tumorigenesis in BRCA1/2 carriers and whether these characteristics are associated with outcomes such as survival and platinum and /or PARP inhibitor sensitivity .