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Science 21 May 1999:
Vol. 284. no. 5418, pp. 1354 - 1356
DOI: 10.1126/science.284.5418.1354
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Reports

BRCA1 Inhibition of Estrogen Receptor Signaling in Transfected Cells

S. Fan, 1* J.-A. Wang, 1 R. Yuan, 1 Y. Ma, 1 Q. Meng, 1 M. R. Erdos, 4 R. G. Pestell, 5 Fang Yuan, 2 K. J. Auborn, 2 I. D. Goldberg, 13 E. M. Rosen 1*

Mutations of the breast cancer susceptibility gene BRCA1 confer increased risk for breast, ovarian, and prostatic cancers, but it is not clear why the mutations are associated with these particular tumor types. In transient transfection assays, BRCA1 was found to inhibit signaling by the ligand-activated estrogen receptor (ER-alpha ) through the estrogen-responsive enhancer element and to block the transcriptional activation function AF-2 of ER-alpha . These results raise the possibility that wild-type BRCA1 suppresses estrogen-dependent transcriptional pathways related to mammary epithelial cell proliferation and that loss of this ability contributes to tumorigenesis.

1 Department of Radiation Oncology,
2 Department of Otolaryngology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, NY 11040, USA.
3 Department of Radiation Oncology, North Shore University Hospital, NSUH-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA.
4 Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 3A14, Bethesda, MD 20892, USA.
5 Departments of Developmental and Molecular Biology and Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
*   To whom correspondence should be addressed.

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S. A. Krum, G. A. Miranda, C. Lin, and T. F. Lane (2003)
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BRCA1 Inhibition of Telomerase Activity in Cultured Cells.
J. Xiong, S. Fan, Q. Meng, L. Schramm, C. Wang, B. Bouzahza, J. Zhou, B. Zafonte, I. D. Goldberg, B. R. Haddad, et al. (2003)
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J. Yun and W.-H. Lee (2003)
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K. J. Auborn, S. Fan, E. M. Rosen, L. Goodwin, A. Chandraskaren, D. E. Williams, D. Chen, and T. H. Carter (2003)
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P. L. Welcsh, M. K. Lee, R. M. Gonzalez-Hernandez, D. J. Black, M. Mahadevappa, E. M. Swisher, J. A. Warrington, and M.-C. King (2002)
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Androgen Receptor Acetylation Governs trans Activation and MEKK1-Induced Apoptosis without Affecting In Vitro Sumoylation and trans-Repression Function.
M. Fu, C. Wang, J. Wang, X. Zhang, T. Sakamaki, Y. G. Yeung, C. Chang, T. Hopp, S. A. W. Fuqua, E. Jaffray, et al. (2002)
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A. R. Venkitaraman (2002)
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W. Fan, S. Jin, T. Tong, H. Zhao, F. Fan, M. J. Antinore, B. Rajasekaran, M. Wu, and Q. Zhan (2002)
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M. Fan, X. Long, J. A. Bailey, C. A. Reed, E. Osborne, E. A. Gize, E. A. Kirk, R. M. Bigsby, and K. P. Nephew (2002)
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p300 Modulates the BRCA1 Inhibition of Estrogen Receptor Activity.
S. Fan, Y. X. Ma, C. Wang, R.-Q. Yuan, Q. Meng, J.-A. Wang, M. Erdos, I. D. Goldberg, P. Webb, P. J. Kushner, et al. (2002)
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BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations.
Q. Ye, Y.-F. Hu, H. Zhong, A. C. Nye, A. S. Belmont, and R. Li (2001)
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S. Nilsson, S. Makela, E. Treuter, M. Tujague, J. Thomsen, G. Andersson, E. Enmark, K. Pettersson, M. Warner, and J.-A. Gustafsson (2001)
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V. G. Vogel (2001)
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BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor.
L. Zheng, L. A. Annab, C. A. Afshari, W.-H. Lee, and T. G. Boyer (2001)
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   Abstract »    Full Text »
Cyclin D1 Binds the Androgen Receptor and Regulates Hormone-Dependent Signaling in a p300/CBP-Associated Factor (P/CAF)-Dependent Manner.
A. T. Reutens, M. Fu, C. Wang, C. Albanese, M. J. McPhaul, Z. Sun, S. P. Balk, O. A. Jänne, J. J. Palvimo, and R. G. Pestell (2001)
Mol. Endocrinol. 15, 797-811
   Abstract »    Full Text »
BRCA1 and BRCA2 and the genetics of breast and ovarian cancer.
P. L. Welcsh and M.-C. King (2001)
Hum. Mol. Genet. 10, 705-713
   Abstract »    Full Text »    PDF »
Ovarian Surface Epithelium: Biology, Endocrinology, and Pathology.
N. Auersperg, A. S. T. Wong, K.-C. Choi, S. K. Kang, and P. C. K. Leung (2001)
Endocr. Rev. 22, 255-288
   Abstract »    Full Text »
Estrogen and the Risk of Breast Cancer.
M. Clemons and P. Goss (2001)
N. Engl. J. Med. 344, 276-285
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Breast Cancer Susceptibility Gene 1 (BRCA1) Is a Coactivator of the Androgen Receptor.
J. J. Park, R. A. Irvine, G. Buchanan, S. S. Koh, J. M. Park, W. D. Tilley, M. R. Stallcup, M. F. Press, and G. A. Coetzee (2000)
Cancer Res. 60, 5946-5949
   Abstract »    Full Text »
Risk of Breast Cancer With Oral Contraceptive Use in Women With a Family History of Breast Cancer.
D. M. Grabrick, L. C. Hartmann, J. R. Cerhan, R. A. Vierkant, T. M. Therneau, C. M. Vachon, J. E. Olson, F. J. Couch, K. E. Anderson, V. S. Pankratz, et al. (2000)
JAMA 284, 1791-1798
   Abstract »    Full Text »    PDF »
Alcohol Stimulates Estrogen Receptor Signaling in Human Breast Cancer Cell Lines.
S. Fan, Q. Meng, B. Gao, J. Grossman, M. Yadegari, I. D. Goldberg, and E. M. Rosen (2000)
Cancer Res. 60, 5635-5639
   Abstract »    Full Text »
Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells.
S. Yeh, Y.-C. Hu, M. Rahman, H.-K. Lin, C.-L. Hsu, H.-J. Ting, H.-Y. Kang, and C. Chang (2000)
PNAS
   Abstract »    Full Text »
Selective Estrogen Receptor Modulators: Structure, Function, and Clinical Use.
C. K. Osborne and S. A. W. Fuqua (2000)
J. Clin. Oncol. 18, 3172-3186
   Abstract »    Full Text »    PDF »
Estrogens, BRCA1, and Breast Cancer.
L. Hilakivi-Clarke (2000)
Cancer Res. 60, 4993-5001
   Abstract »    Full Text »
HET/SAF-B Overexpression Causes Growth Arrest and Multinuclearity and Is Associated with Aneuploidy in Human Breast Cancer.
S. M. Townson, T. Sullivan, Q. Zhang, G. M. Clark, C. K. Osborne, A. V. Lee, and S. Oesterreich (2000)
Clin. Cancer Res. 6, 3788-3796
   Abstract »    Full Text »
Mice Heterozygous for a Brca1 or Brca2 Mutation Display Distinct Mammary Gland and Ovarian Phenotypes in Response to Diethylstilbestrol.
L. M. Bennett, K. A. McAllister, J. Malphurs, T. Ward, N. K. Collins, J. C. Seely, L. C. Gowen, B. H. Koller, B. J. Davis, and R. W. Wiseman (2000)
Cancer Res. 60, 3461-3469
   Abstract »    Full Text »
The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner.
S. Masuda, T. Kobayashi, M. Chikuma, M. Nagao, and R. Sasaki (2000)
Am J Physiol Endocrinol Metab 278, E1038-E1044
   Abstract »    Full Text »    PDF »
The Function of BRCA1 in DNA Damage Response.
J.-S. LEE, K. COLLINS, A. BROWN, C.-H. LEE, and J.H. CHUNG (2000)
Cold Spring Harb Symp Quant Biol 65, 547-552
   Abstract »    PDF »
Tamoxifen Prevention of Breast Cancer: an Instance of the Fingerpost.
S. M. Lippman and P. H. Brown (1999)
J Natl Cancer Inst 91, 1809-1819
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p300 and p300/cAMP-response Element-binding Protein-associated Factor Acetylate the Androgen Receptor at Sites Governing Hormone-dependent Transactivation.
M. Fu, C. Wang, A. T. Reutens, J. Wang, R. H. Angeletti, L. Siconolfi-Baez, V. Ogryzko, M.-L. Avantaggiati, and R. G. Pestell (2000)
J. Biol. Chem. 275, 20853-20860
   Abstract »    Full Text »    PDF »


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