Prevention of BRCA1-mediated mammary tumorigenesis by antiprogesterone.

CS09-03

Mutations in the breast cancer susceptibility gene BRCA1 are associated with an increased risk of breast and ovarian cancers. Reduced BRCA1 expression due to promoter methylation may contribute to breast cancer progression. BRCA1 has been implicated in DNA damage repair, cell cycle checkpoint control and transcriptional regulation. The specific suppression of breast and ovarian carcinogenesis by the pleiotropic BRCA1 tumor suppressor has been hypothesized to be due to its regulation of estrogen receptor α (ERα) and the progesterone receptors (PRs), which play important roles in breast development. However, how the ER and PRs contribute to BRCA1-mediated carcinogenesis remains unclear. We show that Brca1/p53-defective mammary glands of nulliparous miceaccumulate lateral branches and undergo extensive alveologenesis, a phenotype only seen during pregnancy in normal mice. Progesterone receptors (PRs), but not estrogen receptors are over-expressed in the mammary epithelial cells (MECs) of conditional Brca1/p53,but not p53 knockout mice; therefore, progesterone is a potent mitogen for Brca1/p53-defective MECs specifically. PR is stabilized in Brca1/p53-defective MECs. Treatment with anti-progesterone, mifepristone, prevents tumorigenesis in mice carrying mutated Brca1/p53 alleles, indicating a critical role of PR in Brca1-mediated tumorigenesis. These findings uncover a tissue-specific function of BRCA1 and implicate anti-progesterone in breast cancer prevention, especially in BRCA1 carriers. [A. J. P. and Y. L. contributed equally to this work.]