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Loss of Coordinated Androgen Regulation in Nonmalignant Ovarian Epithelial Cells with BRCA1/2 Mutations and Ovarian Cancer Cells¹

Cancer and Blood Research Program, The Hospital for Sick Children [A. E., M. L.]; Division of Reproductive Science, The Samuel Lunenfeld Research Institute, Mt. Sinai Hospital [A. E., T. J. B.]; Divisions of Cancer Informatics [I. J., M. S.] and Gynecology Oncology [K. J. M., B. R.], Ontario Cancer Institute/Princess Margaret Hospital, University Health Network; and the Departments of Zoology [A. E., T. J. B.], Obstetrics and Gynecology [M. L., T. J. B.], Computer Science [I. J.], Medical Biophysics [M. L., I. J.], and Immunology [M. L.], University of Toronto, Toronto, Ontario M5G 1X5, Canada

Epidemiological studies have implicated androgens in the etiology/progression of epithelial ovarian cancer. Because normal and malignant ovarian epithelial cells are growth inhibited by transforming growth factor (TGF) ß, we tested the ability of 5-dihydrotestosterone (DHT) to modulate this response and the expression of TGF-ß receptor types I and II. Cells derived from the ovarian surface epithelium of women undergoing oophorectomy (n = 7) for nonovarian indications or with a germ-line BRCA1 or 2 mutation (n = 9), and from the ascitic fluid of patients with primary ovarian cancer (n = 8) were cultured with and without DHT. Cell proliferation after TGF-ß1 or vehicle treatment was determined, and transcripts for TGF-ß receptors were measured by quantitative reverse transcription-PCR. As low levels of androgen receptor were observed in the cultures, we also measured transcript levels for steroid receptor coactivators SRC-1, ARA70, and AIB1. TGF-ß1 inhibited growth in 12 of 13 cultures tested, and DHT generally reversed this effect, demonstrating that androgens can block TGF-ß-induced growth inhibition in both malignant and nonmalignant ovarian epithelial cells. Transcripts for TGF-ß receptors, SRC-1, and ARA70 were found to be coordinately regulated by androgen in control cells, but not in either malignant or BRCA1/2-positive cell cultures. These findings raise the possibility that by modulating steroid receptor coactivator expression, androgen might affect other hormonal responses and contribute to the initiation of ovarian cancer.

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