title: An estrogen receptor-alpha/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors: repressive effects of p53 on BRCA-1 transcription.
abstract: One of the puzzles in cancer predisposition is that women carrying BRCA-1 mutations preferentially develop tumors in epithelial tissues of the breast and ovary. Moreover, sporadic breast tumors contain lower levels of BRCA-1 in the absence of mutations in the BRCA-1 gene. The problem of tissue specificity requires analysis of factors that are unique to tissues of the breast. For example, the expression of estrogen receptor-alpha (ER alpha) is inversely correlated with breast cancer risk, and 90% of BRCA-1 tumors are negative for ER alpha. Here, we show that estrogen stimulates BRCA-1 promoter activity in transfected cells and the recruitment of ER alpha and its cofactor p300 to an AP-1 site that binds Jun/Fos transcription factors. The recruitment of ER alpha/p300 coincides with accumulation in the S-phase of the cell cycle and is antagonized by the antiestrogen tamoxifen. Conversely, we document that overexpression of wild-type p53 prevents the recruitment of ER alpha to the AP-1 site and represses BRCA-1 promoter activity. Taken together, our findings support a model in which an ER alpha/AP-1 complex modulates BRCA-1 transcription under conditions of estrogen stimulation. Conversely, the formation of this transcription complex is abrogated in cells overexpressing p53.
authors.affiliation: Cancer Biology Interdisciplinary Program, Arizona Health Sciences Center, Tuczon, AZ, USA.
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Jeffy
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Hockings
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Kemp
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Morgan
authors.forename: Jill A
authors.initials: JA
authors.lastname: Hager
authors.forename: Jason
authors.initials: J
authors.lastname: Beliakoff
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Whitesell
authors.forename: G Timothy
authors.initials: GT
authors.lastname: Bowden
authors.forename: Donato F
authors.initials: DF
authors.lastname: Romagnolo
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D004967:Estrogens; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein