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Mechanism of BRCA1-Mediated Inhibition of Progesterone Receptor Transcriptional Activity

Department of Oncology (P.K., Y.M., A.R., S.F., E.M.R.), Lombardi Comprehensive Cancer Center/Georgetown University, and Departments of Radiation Medicine and Biochemistry and Molecular and Cell Biology (E.M.R.), Georgetown University Medical Center, Washington, D.C. 20057

Address all correspondence and requests for reprints to: Dr. Rosen, Department of Oncology, Lombardi Comprehensive Cancer Center/Georgetown University, 3970 Reservoir Road, NW, Box 571469, Washington, D.C. 20057-1469. E-mail: emr36{at}georgetown.edu.

Previously, we reported that BRCA1 inhibits progesterone receptor (PR) activity and blocks progesterone-stimulated gene expression and cell proliferation. In the present manuscript, we studied the mechanism of BRCA1 inhibition of PR activity, using c-Myc as a model progesterone-regulated promoter. Here, we found that BRCA1 has little or no effect on PR ligand-binding affinity. However, BRCA1 overexpression inhibited the R5020-induced recruitment of PR to the c-Myc and mouse mammary tumor virus progesterone response elements (PREs) and blocked R5020-stimulated c-Myc expression, whereas BRCA1 underexpression did the opposite. In EMSAs, BRCA1 overexpression blocked the R5020-induced complex formation between PR and several radiolabeled PRE-containing oligonucleotides, and in vitro-translated BRCA1 blocked the interaction of full-length PR-A or a fragment containing the DNA-binding domain of PR with a radiolabeled PRE oligonucleotide. In further studies, BRCA1 overexpression inhibited the recruitment of coactivators (steroid receptor coactivator 1 and amplified in breast cancer 1) and enhanced the recruitment of a corepressor (histone deacetylase 1) to the c-Myc PRE, whereas BRCA1 knockdown increased the abundance of AIB1 and decreased the abundance of HDAC1 at the c-Myc PRE. These findings suggest that BRCA1 inhibits progestin-stimulated PR activity, in part, by preventing PR from binding to the PRE and by promoting the formation of a corepressor complex rather than a coactivator complex.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR

Coregulators:   BRCA1  |  HDAC1  |  SRC-1  |  GRIP1  |  NCOR  |  SMRT

Ligands:   R5020