title: Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice.
abstract: Germline mutations in the tumor suppressor gene BRCA1 predispose women to breast cancer, however somatic mutations in the gene are rarely detected in sporadic cancers. To understand this phenomenon, we examined mouse models carrying conditional disruption of Brca1 in mammary epithelium in either p53 wild type (wt) or heterozygous backgrounds. Although a p53(+/-) mutation significantly accelerated tumorigenesis, both strains developed mammary tumors in a stochastic fashion, suggesting that multiple factors, in addition to p53 mutations, may be involved in Brca1 related tumorigenesis. A unique feature of Brca1 mammary tumors is their highly diverse histopathology accompanied by severe chromosome abnormalities. The tumors also display extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors, while they were virtually ERalpha and p16 negative. Translocations involving p53 were also identified which lead to abnormal RNA and protein products. In addition, we generated cell lines from mammary tumors and found that the cells retained many of the genetic changes found in the primary tumors, suggesting that these genes may be players in Brca1-associated tumorigenesis. Despite their distinct morphology, all cultured tumor cells were Tamoxifen resistant but highly sensitive to Doxorubicin or gamma-irradiation, suggesting that these methods would be effective in treatment of this disease.
authors.affiliation: Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Brodie
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: W
authors.initials: W
authors.lastname: Qiao
authors.forename: W M
authors.initials: WM
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Cao
authors.forename: C X
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002460:Cell Line; D019925:Cyclin A / Q000096:biosynthesis; D019926:Cyclin B / Q000096:biosynthesis; D056744:Cyclin B1; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000096:biosynthesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005720:Gamma Rays; D019398:Genes, BRCA1; D005838:Genotype; D006579:Heterozygote; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D008677:Metaphase; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000096:biosynthesis; D009124:Muscle Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D016203:CDC2 Protein Kinase; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D019938:Cyclin D1; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004317:Doxorubicin; D008840:Microfilament Proteins; D009124:Muscle Proteins; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C534700:Ccnb1 protein, mouse; C058992:Tagln protein, mouse