Role of BRCA1 in Normal Mammary Epithelial Development and Tumorigenesis

摘要

Germline mutations in BRCAl account for about 45% of all hereditary cases of breast cancer. However, the role of BRCAl in mammary tumorigenesis is not established. My proposal outlines two approaches to extend our knowledge of BRCAl function in normal development and malignant transformation. First, we used the cre-lox system to generate a mouse model in which loss of BRCAl is limited to mammary epithelium. Four different mouse lines expressing the Cre recombinase in mammary epithelium were generated, and we are currently working towards generating a 1ox P-Brca1-lox P mouse. Secondly, we examined synergistic effects between BRCAl and p53 in tumorigenesis. We found that survival of both p53%-/- and p53+/- mice is not altered by BRCAl-deficiency. This suggests that BRCAl does not play a role in the formation of most tumors. Similarly, the survival of the p53+/- mice after exposure to gamma-irradiation was unaltered by BRCAl-deficiency on a mixed genetic background. However, gamma-irradiated p53+/- mice on a BALB/c inbred genetic background showed a significant increase in mammary tumorigenesis as compared to mice on either a DBA/2J or mixed background. These results suggest that genetic factors in BALB/c mice along with environmental stimulus, like ionizing irradiation, play a role in mammary epithelial transformation, in particular, when cells are hemizygous for loss of p53.