TY - JOUR
T1 - An estrogen receptor-α/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors
T2 - Repressive effects of p53 on BRCA-1 transcription
AU - Jeffy, Brandon D.
AU - Hockings, Jennifer K.
AU - Kemp, Michael Q.
AU - Morgan, Sherif S.
AU - Hager, Jill A.
AU - Beliakoff, Jason
AU - Whitesell, Luke J.
AU - Bowden, G. Timothy
AU - Romagnolo, Donato F.
N1 - Funding Information:
Abbreviations: AP-1, activator protein-1; ChIP, chromatin immunoprecipitation; DMEM, Dulbecco’s modified Eagle’s medium; E2, 17h-estradiol; ERa, estrogen receptor-a; ERE, estrogen-responsive element; FCS, fetal calf serum Address all correspondence to: Dr. Donato F. Romagnolo, Laboratory of Mammary Gland Biology, 1177 East 4th Street, Room 303, Shantz Building, The University of Arizona, Tucson, AZ 85721-0038. E-mail: [email protected] 1This study was supported by a National Institutes of Health grant (ES009966, to D.F.R), an Arizona Disease Research Commission grant (8015, to D.F.R.), the Graduate Training Program Grant ES007091 (B.D.J. and J.K.H) and Southwest Environmental Health Sciences Center Grant ES06694 (to D.F.R.). 2Brandon D. Jeffy and Jennifer K. Hockings contributed equally to this work. Received 18 March 2005; Revised 24 May 2005; Accepted 25 May 2005.
PY - 2005/9
Y1 - 2005/9
N2 - 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-α (ERα) is inversely correlated with breast cancer risk, and 90% of BRCA-1 tumors are negative for ERα. Here, we show that estrogen stimulates BRCA-1 promoter activity in transfected cells and the recruitment of ERα and its cofactor p300 to an AP-1 site that binds Jun/Fos transcription factors. The recruitment of ERα/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 ERα to the AP-1 site and represses BRCA-1 promoter activity. Taken together, our findings support a model in which an ERα/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.
AB - 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-α (ERα) is inversely correlated with breast cancer risk, and 90% of BRCA-1 tumors are negative for ERα. Here, we show that estrogen stimulates BRCA-1 promoter activity in transfected cells and the recruitment of ERα and its cofactor p300 to an AP-1 site that binds Jun/Fos transcription factors. The recruitment of ERα/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 ERα to the AP-1 site and represses BRCA-1 promoter activity. Taken together, our findings support a model in which an ERα/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.
KW - AP-1
KW - BRCA-1
KW - ERα
KW - Sporadic breast cancer
KW - p53
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U2 - 10.1593/neo.05256
DO - 10.1593/neo.05256
M3 - Article
C2 - 16229810
AN - SCOPUS:33644508489
SN - 1522-8002
VL - 7
SP - 873
EP - 882
JO - Neoplasia
JF - Neoplasia
IS - 9
ER -