Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice

Germline mutations in the tumor suppressor gene BRCA1 predispose women to b reast cancer, however somatic mutations in the gene are rarely detected in sporadic cancers. To understand this phenomenon, we examined mouse models c arrying conditional disruption of Brca1 in mammary epithelium in either p53 wild type (wt) or heterozygous backgrounds. Although a p53(+/-) mutation s ignificantly accelerated tumorigenesis, both strains developed mammary tumo rs in a stochastic fashion, suggesting that multiple factors, in addition t o p53 mutations, may be involved in Brca1 related tumorigenesis. A unique f eature of Brca1 mammary tumors is their highly diverse histopathology accom panied by severe chromosome abnormalities. The tumors also display extensiv e genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors, while they were virtually ER a lpha and p16 negative. Translocations involving p53 were also identified wh ich lead to abnormal RNA and protein products. In addition, we generated ce ll lines from mammary tumors and found that the cells retained many of the genetic changes found in the primary tumors, suggesting that these genes ma y be players in Brca1-associated tumorigenesis. Despite their distinct morp hology, all cultured tumor cells were Tamoxifen resistant but highly sensit ive to Doxorubicin or irradiation, suggesting that these methods would be e ffective in treatment of this disease.