Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity.

Abstract

The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor alpha (ERalpha)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERalpha binding. Cyclin D1 and BRCA1 were both capable of binding ERalpha in a common region of the ERalpha hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERalpha and for rescue of BRCA1-mediated ERalpha transcriptional repression. In chromatin immunoprecipitation assays, 17beta-estradiol (E2) enhanced ERalpha and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERalpha recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERalpha recruitment at 12 hours. Cyclin D1 expression antagonized BRCA1 inhibition of ERalpha recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERalpha repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.

• Authors: Chenguang Wang, Saijun Fan, Zhiping Li, Maofu Fu, Mahadev Rao, Yongxian Ma, Michael P Lisanti, Chris Albanese, Benita S Katzenellenbogen, Peter J Kushner, Barbara Weber, Eliot M Rosen, Richard G Pestell
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 15 Pg. 6557-67 (Aug 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16061635 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Estrogen Receptor alpha
• Membrane Proteins
• PSEN2 protein, human
• Presenilin-2
• Cyclin D1
• Estradiol
• BRAP protein, human
• Ubiquitin-Protein Ligases

Topics

• Binding, Competitive
• Breast Neoplasms (genetics, metabolism)
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Cyclin D1 (genetics, metabolism, physiology)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (antagonists & inhibitors, genetics, metabolism)
• Female
• Genes, BRCA1
• Humans
• Male
• Membrane Proteins (biosynthesis, genetics)
• Presenilin-2
• Promoter Regions, Genetic
• Prostatic Neoplasms (genetics, metabolism)
• Protein Structure, Tertiary
• Response Elements
• Transcriptional Activation
• Transfection
• Ubiquitin-Protein Ligases