Mammary-Specific Targeting of the BRCA2 Breast Cancer Susceptibility Gene in Mice.

摘要

The breast cancer susceptibility gene Brca2 is known to be responsible for a substantial portion of inherited breast cancer. An appropriate animal model is necessary to determine how specific defects in Brca2 strongly predispose to breast tumorigenesis. We therefore proposed to generate mice carrying a conditional Brca2 mutation whereby Brca2 would be disrupted specifically in the mammary tissue by gene targeting with the Cre-loxP system. We also proposed to generate homozygous Brca2 germline knockout mice. These homozygous Brca2-mutant mice have a significantly increased overall tumor incidence compared to their heterozygous littermates. In addition, a long-term study was initiated to examine the effect of radiation on tumor development in mice with germline mutations of Brca2 and p53. We have found mammary tumor development to occur beginning at seven months of age in animals irradiated at 5 Gy that were hemizygous for both the Brca2 and p53 mutation. Tumor latency appears to be significantly decreased in mice homozygous for the Brca2 exon 27 mutation compared to littermates, regardless of p53 genotype. We believe these distinct animal models will be useful to further clarify the role of Brca2 in mammary tumorigenesis.