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Spontaneous Nf1 deletion and recurrent copy number alterations in mammary tumorigenesis

ABSTRACT: Breast cancer is the most prevalent cancer in women 1, and most cases are believed to have a sporadic, rather than heritable basis 2. To identify breast cancer driver genes, we exploited the C3H-Mcm4Chaos3/Chaos3 (“Chaos3”) mouse model that, by virtue of bearing a defective DNA replicative helicase subunit that causes elevated genomic instability (GIN), sustains somatic alterations ultimately causing mammary adenocarcinomas 6. Array Comparative Genomic Hybridization (aCGH) analysis of Chaos3 mammary tumors revealed recurrent copy number alterations (CNAs), most notably deletion of the Neurofibromin 1 (Nf1) tumor suppressor gene in all cases. NF1, a negative regulator of RAS, is traditionally recognized for its role in driving the development of neurofibromas in the context of the human disease Neurofibromatosis Type 1, but not breast cancer. Genomic DNA from tumor and reference samples were hybridized to NimbleGen 3x720K mouse CGH arrays. Two reference samples were used independently. CNAs were visualized using Nimblegen, IGV, and KCsmart software 32. Select genes were validated via qPCR. Critical regions within each Chaos3 CNA were identified as the region with the greatest overlap across multiple Chaos3 tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE37607 | GEO | 2012/10/01

SECONDARY ACCESSION(S): PRJNA162281

REPOSITORIES: GEO

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Spontaneous Nf1 deletion and recurrent copy number alterations in mammary tumorigenesis

Project description:Breast cancer is the most prevalent cancer in women 1, and most cases are believed to have a sporadic, rather than heritable basis 2. To identify breast cancer driver genes, we exploited the C3H-Mcm4Chaos3/Chaos3 (“Chaos3”) mouse model that, by virtue of bearing a defective DNA replicative helicase subunit that causes elevated genomic instability (GIN), sustains somatic alterations ultimately causing mammary adenocarcinomas 6. Array Comparative Genomic Hybridization (aCGH) analysis of Chaos3 mammary tumors revealed recurrent copy number alterations (CNAs), most notably deletion of the Neurofibromin 1 (Nf1) tumor suppressor gene in all cases. NF1, a negative regulator of RAS, is traditionally recognized for its role in driving the development of neurofibromas in the context of the human disease Neurofibromatosis Type 1, but not breast cancer. Genomic DNA from tumor and reference samples were hybridized to NimbleGen 3x720K mouse CGH arrays. Two reference samples were used independently. CNAs were visualized using Nimblegen, IGV, and KCsmart software 32. Select genes were validated via qPCR. Critical regions within each Chaos3 CNA were identified as the region with the greatest overlap across multiple Chaos3 tumors. Recurring Copy Number Variations (CNVs) for 12 Chaos3 tumors and 2 MMTV-Neu mammary tumors analyzed by aCGH are indicated. Samples analyzed are primary tumors except where indicated.

2012-10-01 | E-GEOD-37607 | biostudies-arrayexpress

Nf1 deletion and recurrent copy number alterations in mammary tumorigenesis

Project description:Breast cancer is the most prevalent cancer in women, and most cases are believed to have a sporadic, rather than heritable basis. Therefore, a major challenge in cancer research is to determine the underlying genomic alterations leading to carcinogenesis and malignancy, and then use this information for personalized therapies. Genomic studies of human cancers that aim to identify causative mutations are complicated by the prevalence of passenger mutations, genetic heterogeneity, and the diversity of breast cancer etiologies and tumor subtypes. Mouse cancer models are powerful for untangling the genomic basis of cancers because genetic and phenotypic variation can be eliminated or controlled. To identify genes contributing to mammary tumorigenesis, we exploited the C3H-Mcm4Chaos3/Chaos3 (“Chaos3”) mouse model that, by virtue of bearing a defective DNA replicative helicase subunit that causes elevated genomic instability (GIN), sustains somatic alterations ultimately causing mammary adenocarcinomas. Genomic analysis of Chaos3 mammary tumors revealed recurrent copy number alterations (CNAs) of specific genomic regions, most notably deletion of the Neurofibromin 1 (Nf1) tumor suppressor gene in all cases. NF1, a negative regulator of RAS, is traditionally recognized for its role in driving the development of neurofibromas in the context of the human disease Neurofibromitosis but not breast cancer. We observed elevated RAS activation and increased sensitivity of both Chaos3 and human Nf1-mutated breast cancer lines to MAPK and/or PI3K/AKT pathway inhibitors. We also found striking overlap between Chaos3 CNAs and human breast cancer CNA data curated in public genomic databases, including Nf1 deletion. Together, our results indicate that spontaneous NF1 loss can drive breast cancer and suggests a potential therapeutic strategy in that subset of patients. reference x sample

2012-08-21 | E-GEOD-36240 | biostudies-arrayexpress

Nf1 deletion and recurrent copy number alterations in mammary tumorigenesis

2012-08-21 | GSE36240 | GEO

CGH analysis of haploid ES cells

Project description:DNA samples of haploid ES cells and control DNA were compared to genomic DNA of the C57B/6 inbred mouse strain on a NimbleGen Mouse CGH 3x720K Whole-Genome Tiling Array (Build MM9), (GPL10989) DNA samples of haploid ES cells and control DNA were compared to genomic DNA of the 129/Sv inbred mouse strain on a NimbleGen Mouse CGH 3x720K Whole-Genome Tiling Array (Build MM9), (GPL10989)

2011-07-23 | GSE30749 | GEO

Nf1 Deficiency Increases Mammary Collagen Deposition and Restricts Adipocyte Differentiation Before Tumor Formation

Project description:BACKGROUND: The NF1 tumor suppressor gene is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1) – a tumor predisposition syndrome caused by a germline NF1 mutation – have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanisms by which NF1 mutation leads to breast cancer tumorigenesis are not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. METHODS: To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development and develops highly penetrant breast cancer. RESULTS: We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient rat mammary mature adipocytes have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation but flow cytometry analysis did not show a change mammary adipose-derived mesenchymal stem cell abundance. CONCLUSION: Collectively, these studies uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary gland will create a foundation for developing early detection strategies of breast cancer among NF1 patients.

2023-05-08 | GSE231603 | GEO

Copy Number Abnormalities in Canine Mammary Cancers

Project description:Spontaneously occurring canine mammary cancer (MC) represents an excellent model of human breast cancer, but is greatly understudied. We performed high density arrays on 12 canine MC cases, including 7 simple carcinomas and four complex carcinomas. Simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many faithfully recapitulating key features of human breast cancer. Complex carcinomas, with luminal and myoepithelial cells both proliferating (which is rare in human breast cancer), appear to lack genomic abnormalities. Comparison of CNAs from canine mammary simple carcinomas and complex carcinomas

2014-09-07 | E-GEOD-54535 | biostudies-arrayexpress

Affymetrix OncoScan CN analysis on breast cancer in women affected with Neurofibromatosis type 1

Project description:NF1 germline mutation predisposes to breast cancer. NF1 mutations have also been proposed as oncogenic drivers in sporadic breast cancers. To understand the genomic and histological characteristics of these breast cancers, we examined the tumors with NF1 germline mutations.

2018-07-20 | GSE115890 | GEO

CGH analysis of chemical induced pluripotent stem cells

Project description:Comparative genomic hybridization (CGH) analysis of CiPSCs (clone CiPS-57 and CiPS-58) and OSKM-iPSCs. C57BL/6 mouse embryonic fibroblasts (MEFs) genome DNA as a reference. No consistent copy number variations (CNVs) among CiPSCs and OSKM-iPSCs. Genome DNA of CiPSCs and OSKM-iPSCs (both of them induced form C57BL/6 MEFs) was isolated and compared with C57BL/6 MEFs genomic DNA reference by the NimbleGen Mouse CGH 3x720K Whole-Genome Tiling Array.

2013-07-22 | E-GEOD-48231 | biostudies-arrayexpress

CGH analysis of androgenetic haploid embryonic stem cells

Project description:Comparative genomic hybridization (CGH) analysis of androgenetic haploid embryonic stem cells was done with 129/Sv male mouse kidney genomic DNA as reference. The results revealed no consistent copy number variations (CNVs) among the examined cell lines (AH129-5, AH129-N1 and AH129-NC1), except for the global difference on the X chromosome to the male control. Genomic DNA of FACS sorted G0/G1 stage ahES cells was compared with 129/Sv male mouse kidney genomic DNA reference by the NimbleGen Mouse CGH 3x720K Whole-Genome Tiling Array (Build MM9) [100718_MM9_WG_CGH_HX3]

2012-08-30 | E-GEOD-39390 | biostudies-arrayexpress

Comparative genomic hybridization of breast tumors to identify links between copy number alterations and specific clinicopathological parameter

Project description:Breast cancer is a leading cause of cancer-death among women, where the clinicopathological features of tumors are used to prognosticate and guide therapy. DNA copy number alterations (CNAs), which occur frequently in breast cancer and define key pathogenetic events, are also potentially useful prognostic or predictive factors. Here, we report a genome-wide array-based comparative genomic hybridization (array CGH) survey of CNAs in 89 breast tumors from a patient cohort with locally advanced disease. Statistical analysis links distinct cytoband loci harboring CNAs to specific clinicopathological parameters, including tumor grade, estrogen receptor status, presence of TP53 mutation, and overall survival. Notably, distinct spectra of CNAs also underlie the different subtypes of breast cancer recently defined by expression-profiling, implying these subtypes develop along distinct genetic pathways. In addition, higher numbers of gains/losses are associated with the "basal-like" tumor subtype, while high-level DNA amplification is more frequent in "luminal-B" subtype tumors, suggesting also that distinct mechanisms of genomic instability might underlie their pathogenesis. The identified CNAs may provide a basis for improved patient prognostication, as well as a starting point to define important genes to further our understanding of the pathobiology of breast cancer.

2006-12-01 | E-SMDB-3878 | biostudies-arrayexpress

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