Tumor and Stem Cell Biology BRCA1 Counteracts Progesterone Action by Ubiquitination Leading to Progesterone Receptor Degradation and Epigenetic Silencing of Target Promoters

Germ-line mutations in the BRCA1 gene increase the risk of breast cancer in women, but the precise mechanistic basis for this connection remains uncertain. One popular hypothesis to explain breast tissue specificity postulates a link between BRCA1 and the action of the ovarian hormones estrogen and progesterone. Given the relevance of progesterone for normal mammary development and breast cancer formation, we searched for a functional relationship between BRCA1 and progesterone receptor (PR) in the PR-positive breast cancer cell line T47D. Here, we report that BRCA1 inhibits the transcriptional activity of PR by at least 2 mechanisms involving the E3 ubiquitin ligase activity of BRCA1. First, BRCA1 has a direct effect on the cellular level of PR and, hence, on the extent of PR recruitment to target promoters through the promotion of its ligandindependent and -dependent degradation. Through in vitro and in vivo assays, we found that BRCA1/BARD1may be the main E3 ubiquitin ligase responsible for ubiquitination and degradation of PR in the absence of hormone. Second, after hormone treatment of cells, the BRCA1/BARD1 complex is recruited via interaction with PR to the hormone-responsive regions of PR target genes, affecting local levels of monoubiquitinated histone H2A and contributing to epigenetic silencing of these promoters. The connections between BRCA1/BARD1 and PR activity suggested by our findings may help explain why host mutations in BRCA1 exert a tissue specificity in preferentially elevating the risk of breast cancer. Cancer Res; 71(9); 3422–31. 2011 AACR.