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-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 873-882 |
| Number of pages | 10 |
| Journal | Neoplasia |
| Volume | 7 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2005 |
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Keywords
- AP-1
- BRCA-1
- ERα
- p53
- Sporadic breast cancer
ASJC Scopus subject areas
- Cancer Research
Cite this
An estrogen receptor-α/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. / Jeffy, Brandon D.; Hockings, Jennifer K.; Kemp, Michael Q.; Morgan, Sherif S.; Hager, Jill A.; Beliakoff, Jason; Whitesell, Luke J.; Bowden, G. Timothy; Romagnolo, Donato.
In: Neoplasia, Vol. 7, No. 9, 09.2005, p. 873-882.Research output: Contribution to journal › Article
}
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
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 - p53
KW - Sporadic breast cancer
UR - http://www.scopus.com/inward/record.url?scp=33644508489&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644508489&partnerID=8YFLogxK
U2 - 10.1593/neo.05256
DO - 10.1593/neo.05256
M3 - Article
VL - 7
SP - 873
EP - 882
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 9
ER -