Mouse models of hereditary breast cancer

Hereditary breast cancer is frequently due to germline mutations in the breast cancer susceptibility gene BRCA1, whose protein product has been implicated in a variety of cellular pathways. The mechanism of tumor suppression remains elusive. BRCA1 forms a heterodimeric complex with the related BARD1 protein and its ubiquitin ligase activity is largely dependent upon this interaction. Inactivation of Bard1 in mice results in early embryonic lethality and chromosomal instability, similar to Brca1 inactivation. To overcome this lethality and study these genes in mammary tumorigenesis, we employed the cre/loxP system to inactivate conditional Bard1 and Brca1 alleles in mammary epithelial cells. Ablation of either Bard1 or Brca1 resulted in a high incidence of mammary tumors with an average latency of ∼14 months. Comparative analysis of these tumors by histopathology, immunohistochemistry, cytogenetics, p53 mutation analysis and gene expression profiling revealed a striking similarity between the tumor phenotypes, suggesting that the biological functions attributed to BRCA1, including those responsible for tumor suppression, are likely mediated by the BRCA1/BARD1 heterodimer.; The p53 tumor suppressor has also been implicated in hereditary breast cancer, as p53 mutations are frequently found in BRCA1 tumors. In addition, people who suffer from the Li-Fraumeni syndrome harbor gem-dine p53 mutations, and often present with breast cancer. To test the hypothesis that inactivation of p53 is a necessary step in BRCA-associated tumorigenesis we also assessed tumor development in conditional Bard1/p53 and Brca1/p53 double mutant mice. Concomitant inactivation of these genes resulted in tumor development with high incidence, sarcoma-like pathology, and significantly reduced latency. To examine the role of p53 in mammary tumorigenesis, the gene was inactivated alone, and these p53 tumors exhibit a distinct histopathological, cytogenetic, and microarray profile. Rather than presenting as carcinomas, as seen in the Bard1 and Brca1 analysis, these tumors are sarcomas, and downregulate epithelial markers such as E-cadherin, and upregulate mesenchymal markers, like vimentin. Taken together, these results suggest a cooperative mechanism between the p53 and BARD1/BRCA1 pathway, as well as a general sensitivity of breast tissue to loss of any one of these genes.