Abstract
The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-α] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-α activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-α activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-α in vivo and to bind to ER-α in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-α. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-α binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-α activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-α, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain.
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References
Chapman MS and Verma IM. . 1996 Nature 382: 678–679.
Chen Y, Lee WH and Chew HK. . 1999 J. Cell. Physiol. 181: 385–392.
Chlebowski RT. . 2000 N. Engl. J. Med. 343: 191–198.
Dignam JD, Lebovitz RM and Roeder RG. . 1983 Nucleic Acids Res. 5: 1475–1489.
Fan S, Wang J-A, Meng Q, Yuan R-Q, Ma YX, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID and Rosen EM. . 1999 Science 284: 1354–1356.
Fan S, Wang J-A, Yuan R-Q, Ma YX, Meng Q, Goldberg ID and Rosen EM. . 1998 Oncogene 16: 3069–3083.
Faust PL, Kornfeld S and Chirgwin JM. . 1985 Proc. Natl. Acad. Sci. USA 82: 4910–4914.
Ford D, Easton DF, Bishop DT, Narod SA and Goldgar DE. . 1994 Lancet 343: 692–695.
Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE and King MC. . 1994 Nat. Genet. 8: 399–404.
Henttu PMA, Kalkhoven E and Parker MG. . 1998 Mol. Cell. Biol. 17: 1832–1839.
Jeltsch JM, Robers C, Shatz JM, Garnier JM, Brown AM and Chambon P. . 1987 Nucleic Acids Res. 15: 1401–1414.
Loman N, Johannsson O, Bendahl PO, Borg A, Ferno M and Olsson H. . 1998 Cancer 83: 310–319.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cichran C, Bennett LM, Ding W. . 1994 Science 266: 66–71.
Monteiro AN, August A and Hanafusa H. . 1996 Proc. Natl. Acad. Sci. USA 93: 13595–13599.
Streuwing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC and Tucker MA. . 1997 New Engl. J. Med. 336: 1401–1408.
Tirkonnen M, Johannson O, Agnarsson BA, Olsson H, Ingvar-sson S, Karbu R, Tanner M, Isola J, Barkardottir RB, Borg A and Kallioniemi OP. . 1997 Cancer Res. 57: 1222–1227.
Wang CY, Petryniak B, Thompson CB, Kaelin WG and Leiden JM. . 1993 Science 260: 1330–1335.
Webb P, Nguyen P, Shinsako J, Anderson C, Feng W, Nguyen MP, Chen D, Huang SM, Subramanian S, McKinerney E, Katzenellenbogen BS, Stallcup MR and Kushner PJ. . 1998 Mol. Endocrinol. 12: 1605–1618.
Webber MM, Bello D and Quader S. . 1997 Prostate 30: 58–64.
Yarden RI and Brody LC. . 1999 BRCA1 interacts with components of the histone deacetylase complex Proc. Natl. Acad. Sci. USA 96: 4893–4988.
Yu X, Wu LC, Bowcock AM, Aronheim A and Baer R. . 1998 J. Biol. Chem. 273: 25388–25392.
Acknowledgements
Supported, in part, by USPHS grants R01-ES09169, R01-82599, and RO1-80000 (EMR.), the Elsa U Pardee Cancer Foundation of Michigan (EMR), the New York State Department of Health (EMR), US Army Breast Cancer grant DAMD17-99-1-9254 (EM Rosen), the Susan G. Komen Breast Cancer Foundation (RG Pestell), and USPHS grants RO1-CA75503 and R01-CA70897 (RG Pestell).
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Fan, S., Ma, Y., Wang, C. et al. Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene 20, 77–87 (2001). https://doi.org/10.1038/sj.onc.1204073
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DOI: https://doi.org/10.1038/sj.onc.1204073
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