Mouse models for BRCA1-associated breast cancer

Breast tumor suppressor gene 1 (BRCA1) is a well-known transcription regulator, mutations of which cause tumor formation in a tissue-specific manner. In the past years, we have studied functions of Brca1 in mouse models carrying a number of different mutations. We showed that impaired Brca1 function causes chromosome damages, failure of the G2/M cell cycle checkpoint, and centrosome amplification, leading to p53-dependent lethality. Our further analysis revealed that Brca1 also plays an important role in spindle checkpoint through regulating Mad2. We showed that mice carrying a targeted disruption of Brca1 in mammary epithelium developed mammary tumors at low frequency after long latency and the tumorigenesis was significantly accelerated in a p53^+/- genetic background. Mammary tumors were highly diverse in histopathology and displayed extensive genetic/molecular alterations, including overexpression of ErbB2, c-myc, p27 and cyclin D₁, and downregulation of p16. The most noticeable change is expression of estrogen receptor alpha (ERα). We showed that the absence of Brca1 resulted in increased expression of ERα in epithelial cells at pre-malignant stages and initiating tumors. However, expression of ERα was diminished in tumors of more advanced stages. This observation suggests that ERα-mediated signals are involved in tumorigenesis. Finally, we provided evidence that BRCA1 affects the MAPK pathway through interacting with estrogen/ERα signals, which may account for tissue-specific tumorigenesis.