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

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) , we tested the ability of 5 -dihydrotestosterone (DHT) to modulate this response and the expression of TGFreceptor 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 TGF1 or vehicle treatment was determined, and transcripts for TGFreceptors 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. TGF1 inhibited growth in 12 of 13 cultures tested, and DHT generally reversed this effect, demonstrating that androgens can block TGF-induced growth inhibition in both malignant and nonmalignant ovarian epithelial cells. Transcripts for TGFreceptors, 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.