ANDROGENS INFLUENCE ESTROGEN-INDUCED RESPONSES IN HUMAN BREAST-CARCINOMA CELLS THROUGH CYTOCHROME-P450 AROMATASE

The aromatase cytochrome P450 complex is responsible for the in vivo c onversion of androgens to estrogens. Although breast cancer epithelial cells have been reported to have appreciable aromatase activity, its biologic significance remains uncertain. To address this, the effect o f androgens on the expression of the estrogen-regulated gene pS2 in ho rmone-dependent human breast carcinoma cells in vitro was examined. St eroid-deprived MCF-7 cells were exposed to varying concentrations (1 n M, 10 nM, and 100 nM of androstenedione or testosterone for 2, 4, and 6 days. Baseline aromatase activity was 4.9 (+/-3.1) fmol (H2O)-H-3/ho ur/mu g DNA [34.3 (+/-21.3) fmol/hr/10(6) cells] and was not influence d by the androgens. As an indication of estrogen biosynthesis, norther n analysis was performed to quantitate pS2 mRNA expression. Although n o significant pS2 induction was observed at 2 days, both 4 and 6 day e xposure to 100 nM testosterone resulted in a 3-fold increase in pS2 mR NA expression. 5 alpha-dihydrotestosterone (5 alpha-DHT) failed to eli cit a similar pS2 response. This testosterone-induced response was inh ibited with the aromatase inhibitor 7 alpha(4'-amino) phenylthio-1,4-a ndrostadiene-3,17-dione (7 alpha-APTADD) and with 10 mu M tamoxifen. M CF-7 breast cancer cells possess endogenous aromatase activity at high enough levels to convert androgens to estrogens and elicit an estroge n-induced response. The expression of aromatase may offer a potential advantage to hormone-responsive cells, providing an additional autocri ne growth pathway which may be exploited.