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

Abstract

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/BARD1 may 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. Ó2011 AACR.

Effect of BRCA1 on epidermal growth factor receptor in ovarian cancer

“…A growing body of evidence suggests that BRCA1 has extensive cellular effects on hormone receptor signaling pathways. For example, BRCA1 can inhibit progesterone receptor (PR) activity in the PR-positive human breast cancer cell line T47D [17,18] and repress estrogen receptor-alpha activity in MCF-7 cells [19]. BRCA1 may also be a potential regulator of the insulin-like growth factor 1 receptor in human breast cancer cell line HCC1937 [20].…”

Ubiquitylation of nuclear receptors: new linkages and therapeutic implications

“…BRCA1, along with its partner BARD1, form a heterodimeric RING E3 ligase implicated in numerous cellular processes including DNA repair, cell cycle control, transcriptional regulation, apoptosis, and genomic stability (Deng 2006; Roy et al 2012). BRCA1 ubiquitylation of both ERα and PR contributes to the their transcriptional function (Eakin et al 2007; Calvo & Beato 2011). BRCA1/BARD1 monoubiquitylates ERα in vitro and in vivo (Eakin et al 2007; Dizin & Irminger-Finger 2010; Ma et al 2010; Zhu et al 2014).…”

“…It should be noted, however, that BRCA1 mutant breast cancers are almost always ERα-negative and thus potential therapies targeting the interaction between ERα and BRCA1 would not be suitable in these cases (Karp et al 1997; Loman et al 1998). In the case of PR, BRCA1 induces ubiquitylation but whether PR ubiquitylation is polyubiquitylation (attachment of a ubiquitin chain on a lysine) or multi-monoubiquitylation (multiple single ubiquitin attachments on different lysine sites on the substrate) is unresolved (Calvo & Beato 2011). …”

Role of BRCA1 in Breast Cancer Metastasis

“…The RING domain of BRCA1 with a ring finger consists of seven cysteine and one histidine residues critically coordinate with Zn atoms, which actually stabilizes the RING structure [8,9]. BARD1, a protein that is structurally homologous to the BRCA1 RING domain, interacts with the RING domain of BRCA1 and is critically important for the ubiquitin ligase activity, and it is reported to ubiquitinate several target proteins for degradation such as ER alpha, progesterone receptor, histone H2A, and CtIP [10][11][12]. It also modulates the nuclear import and export of BRCA1 [13,14].…”