Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

Sex steroids play important roles in the development of many human breast carcinomas, and aromatase inhibitors are used for the anti-estrogen therapy. Recent studies have demonstrated that aromatase suppressed 5alpha-dihydrotestosterone (DHT) synthesis in breast carcinoma cells, but intratumoral concentration of androgens and its significance have not been reported in the breast carcinoma patients treated with aromatase inhibitors. Therefore, we examined androgen concentrations in breast carcinoma tissues treated with exemestane, and further performed in vitro studies to characterize the significance of androgen actions. Intratumoral DHT concentration was significantly higher in breast carcinoma tissues following exemestane treatment (n=9) than those without the therapy (n=7), and 17beta-hydroxysteroid dehydrogenase type 2 (17betaHSD2) status was significantly altered to be positive after the treatment. Following in vitro studies showed that 17betaHSD2 expression was dose dependently induced by both DHT and exemestane in T-47D breast carcinoma cells, but these inductions were not additive. DHT-mediated induction of 17betaHSD2 expression was markedly suppressed by estradiol (E(2)) in T-47D cells. E(2)-mediated cell proliferation was significantly inhibited by DHT in T-47D cells, associated with an increment of 17betaHSD2 expression level. These findings suggest that intratumoral androgen actions are increased during exemestane treatment. 17betaHSD2 is a potent DHT-induced gene in human breast carcinoma, and may not only be involved in anti-proliferative effects of DHT on breast carcinoma cells but also serve as a potential marker for response to aromatase inhibitor in the breast carcinoma patients.