Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Nf1 deletion and recurrent copy number alterations in mammary tumorigenesis

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Charles Perou

PROVIDER: E-GEOD-36240 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Mandibular and molar vascularization in guinea pigs. Scanning electron microscopic study of corrosion casts.

Aharinejad S S Franz P P Firbas W W Fakhari M M

The Anatomical record 19901201 4

The vascularization of the mandible, molar teeth, and periodontal ligament of adult male and female albino guinea pigs (Cavia porcellus) was studied by scanning electron microscopy of vascular corrosion casts. Main routes of mandibular blood supply and drainage are shown, and the intrinsic vascular patterns of the mandible, the molars, and the periodontal ligament are described. Results are compared to findings in man and in other mammals. ...[more]

PMID: 2285164

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Project description:Background: Human breast cancer is a heterogeneous disease consisting of multiple molecular subtypes. Genetically engineered mouse models (GEMMs) are useful resources for studying breast cancers in vivo under genetically controlled and immune competent conditions. Identifying murine models with conserved human tumor features will facilitate etiology determinations, highlight the effects of mutations on pathway activation, and improve preclinical drug validation. Results: Transcriptomic profiles of 27 murine models of mammary carcinoma and normal mammary tissue were determined using gene expression microarrays. Hierarchical clustering analysis identified 17 distinct murine subtypes (classes). Across species analyses using three independent human breast cancer datasets identified eight murine classes that represent specific human breast cancer subtypes. Multiple models were associated with human basal-like tumors including TgC3(1)-Tag, TgWap-Myc, and Trp53-/-. Interestingly, the TgWAPCre-Etv6 model mimicked the HER2-enriched subtype, a group of human tumors without a murine counterpart in previous comparative studies. Gene signature analysis identified hundreds of commonly expressed pathways between linked mouse and human subtypes, highlighting potentially common genetic drivers of tumorigenesis and candidate pathways for therapeutic intervention. Conclusion: This study consolidates murine models of breast carcinoma into the largest comprehensive transcriptomic dataset to date to identify human-mouse disease subtype counterparts. This approach illustrates the value of comparisons between species to identify murine models that faithfully mimic the human condition and indicates that multiple GEMMs are needed to represent the diversity of human breast cancers. These trans-species associations should guide model selection during preclinical study design to ensure appropriate representatives of the human disease subtypes are used. Keywords: breast cancer, comparative genomics, genetically engineered mouse models, and molecular pathway signatures reference x sample

Project description:Introduction: In breast cancers, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations as well, as shown by a previously described micro-event in the PTEN gene in the Basal-like SUM149 breast cancer cell line. Methods: We sought to identify if small regions of genomic change exist by using a high density, gene centric Comparative Genomic Hybridizations (CGH) array on both cell lines and primary tumors. A custom Agilent tiling array for CGH (244,000 probes, 200bp tiling resolution) was created to identify small regions of genomic change and was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments being called micro-aberrations (<64 contiguous probes, ~ <15kb). Results: Our data showed that primary tumor breast cancer genomes frequently contained areas of small-scale copy number gains and losses, termed micro-aberrations, which are undetectable using lower-density genome-wide platforms. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene as suggested by data from microarray and mRNA-seq studies. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5’ regions of the affected genes, including the promoter region, and a high frequency of micro-aberrations was associated with poor survival outcomes. Conclusion: Using a high probe density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that contribute to gene inactivation, and thus, genomic instability and tumor formation through a mechanism not detected using conventional copy number analyses. reference x sample

Dataset Information

Nf1 deletion and recurrent copy number alterations in mammary tumorigenesis

Publications

Mandibular and molar vascularization in guinea pigs. Scanning electron microscopic study of corrosion casts.

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