title: 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.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia 20007, USA.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Maofu
authors.initials: M
authors.lastname: Fu
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Yongxian
authors.initials: Y
authors.lastname: Ma
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kushner
authors.forename: Barbara
authors.initials: B
authors.lastname: Weber
authors.forename: Eliot M
authors.initials: EM
authors.lastname: Rosen
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D053766:Presenilin-2; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020218:Response Elements; D015533:Transcriptional Activation; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D019938:Cyclin D1; D004958:Estradiol; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases