Loss of coordinated androgen regulation in nonmalignant ovarian epithelial cells with BRCA1/2 mutations and ovarian cancer cells.

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) beta, we tested the ability of 5alpha-dihydrotestosterone (DHT) to modulate this response and the expression of TGF-beta 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-beta1 or vehicle treatment was determined, and transcripts for TGF-beta 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-beta1 inhibited growth in 12 of 13 cultures tested, and DHT generally reversed this effect, demonstrating that androgens can block TGF-beta-induced growth inhibition in both malignant and nonmalignant ovarian epithelial cells. Transcripts for TGF-beta 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.