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Molecular and Cellular Biology, July 2004, p. 5900-5913, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5900-5913.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

BRCA1 Inhibits Membrane Estrogen and Growth Factor Receptor Signaling to Cell Proliferation in Breast Cancer

Mahnaz Razandi,1,2 Ali Pedram,1,2 Eliot M. Rosen,3 and Ellis R. Levin1,2,4*

Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, California 90822,1 Departments of Medicine,2 Pharmacology, University of California, Irvine, Irvine, California 92717,4 Department of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 110403

Received 28 October 2003/ Returned for modification 16 December 2003/ Accepted 6 April 2004

BRCA1 mutations and estrogen use are risk factors for the development of breast cancer. Recent work has identified estrogen receptors localized at the plasma membrane that signal to cell biology. We examined the impact of BRCA1 on membrane estrogen and growth factor receptor signaling to breast cancer cell proliferation. MCF-7 and ZR-75-1 cells showed a rapid and sustained activation of extracellular signal-related kinase (ERK) in response to estradiol (E2) that was substantially prevented by wild-type (wt) but not mutant BRCA1. The proliferation of MCF-7 cells induced by E2 was significantly inhibited by PD98059, a specific ERK inhibitor, or by dominant negative ERK2 expression and by expression of wt BRCA1 (but not mutant BRCA1). E2 induced the synthesis of cyclins D1 and B1, the activity of cyclin-dependent kinases Cdk4 and CDK1, and G1/S and G2/M cell cycle progression. The intact tumor suppressor inhibited all of these. wt BRCA1 also inhibited epidermal growth factor and insulin-like growth factor I-induced ERK and cell proliferation. The inhibition of ERK and cell proliferation by BRCA1 was prevented by phosphatase inhibitors and by interfering RNA knockdown of the ERK phosphatase, mitogen-activated kinase phosphatase 1. Our findings support a novel tumor suppressor function of BRCA1 that is relevant to breast cancer and identify a potential interactive risk factor for women with BRCA1 mutations.

* Corresponding author. Mailing address: Medical Service (111-I), Long Beach VA Medical Center/UC—Irvine, 5901 E. 7th St., Long Beach, CA 90822. Phone: (562) 826-5748. Fax: (562) 826-5515. E-mail: ellis.levin{at}med.va.gov.

Molecular and Cellular Biology, July 2004, p. 5900-5913, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5900-5913.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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