Mechanism of BRCA1-mediated inhibition of progesterone receptor transcriptional activity.
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.
Katiyar
Pragati
P
Department of Oncology, Lombardi Comprehensive Cancer Center/Georgetown University, Washington, D.C. 20057-1469, USA.
Ma
Yongxian
Y
Riegel
Anna
A
Fan
Saijun
S
Rosen
Eliot M
EM
D019313:BRCA1 Protein / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005822:Genetic Vectors; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008957:Models, Genetic; D009841:Oligonucleotides / Q000235:genetics; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020218:Response Elements; D014158:Transcription, Genetic
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D008024:Ligands; D009841:Oligonucleotides; D016271:Proto-Oncogene Proteins c-myc; D011980:Receptors, Progesterone