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Role of direct interaction in BRCA1 inhibition of estrogen receptor activity

Oncogene volume 20, pages 77–87 (2001)Cite this article

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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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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Authors and Affiliations

  1. Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, New York, 11040, NY, USA

    Saijun Fan, Yong Xian Ma, Ren-qi Yuan, Qinghui Meng, Ji-An Wang, Itzhak D Goldberg & Eliot M Rosen

  2. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, NY, USA

    Chenguang Wang & Richard G Pestell

  3. Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, NY, USA

    Chenguang Wang, Richard G Pestell & Eliot M Rosen

  4. Division of Human Endocrine Tumor Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, NY, USA

    Michael Erdos, Richard G Pestell & Eliot M Rosen

  5. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 3A14, Bethesda, 20892, Maryland, MD, USA

    Paul Webb

  6. Metabolic Research Unit, University of California, San Francisco, UC School of Medicine, HSW 1119, San Francisco, 94143-0540, California, CA, USA

    Peter J Kushner

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  1. Saijun Fan
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  2. Yong Xian Ma
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  3. Chenguang Wang
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  4. Ren-qi Yuan
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  7. Michael Erdos
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  8. Itzhak D Goldberg
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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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