title: Down-regulation of transforming growth factor beta receptors by androgen in ovarian cancer cells.
abstract: 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 beta (TGF-beta), we tested whether steroid hormones could regulate the expression of TGF-beta1 or its receptors in ovarian cancer cells, as assessed by quantitative reverse transcription-PCR. Treatment of ovarian cancer HEY cells with 500 nM 5alpha-dihydrotestosterone (DHT), but not estradiol-17beta or progesterone, for 60 h down-regulated the expression of mRNA for TGF-beta receptors I and II (TbetaR-I and TbetaR-II), betaglycan, and endoglin but had no effect on TGF-beta1 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 TbetaR-II mRNA. The AR antagonist hydroxyflutamide did not reverse the effect of DHT on SKOV-3 cells but by itself down-regulated TbetaR-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-beta1 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-beta receptor levels, thereby allowing ovarian cancer cells to escape TGF-beta1 growth inhibition.
authors.affiliation: Blood & Cancer Research Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Evangelou
authors.forename: S K
authors.initials: SK
authors.lastname: Jindal
authors.forename: T J
authors.initials: TJ
authors.lastname: Brown
authors.forename: M
authors.initials: M
authors.lastname: Letarte
mesh_terms: D013196:Dihydrotestosterone / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D011944:Receptors, Androgen; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D005485:Flutamide