Mechanism of BRCA1-mediated inhibition of progesterone receptor transcriptional activity.

Abstract

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.

• Authors: Pragati Katiyar, Yongxian Ma, Anna Riegel, Saijun Fan, Eliot M Rosen
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 23 Issue 8 Pg. 1135-46 (Aug 2009) ISSN: 1944-9917 [Electronic] United States
• PMID: 19389812 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• Ligands
• Oligonucleotides
• Proto-Oncogene Proteins c-myc
• Receptors, Progesterone

Topics

• BRCA1 Protein (physiology)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation
• Genetic Vectors
• Humans
• Ligands
• Models, Biological
• Models, Genetic
• Oligonucleotides (genetics)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-myc (metabolism)
• Receptors, Progesterone (antagonists & inhibitors, metabolism)
• Response Elements
• Transcription, Genetic