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[Cancer Research 60, 929-935, February 15, 2000]
© 2000 American Association for Cancer Research

Endocrinology

Down-Regulation of Transforming Growth Factor ß Receptors by Androgen in Ovarian Cancer Cells1

Andreas Evangelou, Sangita K. Jindal2, Theodore J. Brown and Michelle Letarte3

Blood & Cancer Research Program, The Hospital for Sick Children [A. E., M. L.], Division of Reproductive Science, The Samuel Lunenfeld Research Institute, Mt. Sinai Hospital [T. J. B.], and Department of Zoology [A. E., T. J. B.], Institute of Medical Sciences [S. K. J.], Department of Obstetrics and Gynecology [T. J. B., M. L.], and Department of Immunology [M. L.], University of Toronto, Toronto, Ontario M5G 1X8, Canada

Steroid hormones have been implicated in the etiology and/or progression of epithelial ovarian cancer. As ovarian surface epithelial cells are growth inhibited by transforming growth factor ß (TGF-ß), we tested whether steroid hormones could regulate the expression of TGF-ß1 or its receptors in ovarian cancer cells, as assessed by quantitative reverse transcription-PCR. Treatment of ovarian cancer HEY cells with 500 nM 5{alpha}-dihydrotestosterone (DHT), but not estradiol-17ß or progesterone, for 60 h down-regulated the expression of mRNA for TGF-ß receptors I and II (TßR-I and TßR-II), betaglycan, and endoglin but had no effect on TGF-ß1 mRNA levels. Androgen receptor (AR) mRNA expression in HEY cells was compared to other ovarian cancer cell lines. OVCAR-3 cells expressed AR mRNA levels similar to that of androgen-responsive LNCaP prostate cancer cells, whereas SKOV-3 and HEY cells expressed only 3 and 0.01%, respectively. Western blot analysis and saturation binding assays confirmed the expression of AR protein in these three cell lines, but at the limit of detection in SKOV-3 and HEY cells. Treatment of SKOV-3 and HEY cells for 24 h with 1–50 nM DHT resulted in a dose-dependent down-regulation of TßR-II mRNA. The AR antagonist hydroxyflutamide did not reverse the effect of DHT on SKOV-3 cells but by itself down-regulated TßR-II mRNA. This apparent androgen-mimetic action of hydroxyflutamide and the ability of SKOV-3 and HEY cells to respond to DHT may be due to their expression of AR-associating protein 70, an AR co-activator reported to amplify AR transactivation and to result in agonist activity of AR antagonists. DHT was able to reverse TGF-ß1 growth-inhibitory action in SKOV-3 cells and in a primary culture of ovarian cancer cells derived from ascites. Thus, androgens may promote ovarian cancer progression in part by decreasing TGF-ß receptor levels, thereby allowing ovarian cancer cells to escape TGF-ß1 growth inhibition.




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