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Androgenic Control of Transforming Growth Factor-β Signaling in Prostate Epithelial Cells through Transcriptional Suppression of Transforming Growth Factor-β Receptor II

¹ Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, ² Department of Pharmacology, and ³ Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio; and ⁴ Lee Gil Ya Cancer Center and Diabetes Institute, Gachon University of Medicine and Science, Songdo, Korea

Requests for reprints: David Danielpour, Wolstein Research Building, Room 3-532, 2103 Cornell Avenue, Cleveland, OH 44106. Phone: 216-368-5670; Fax: 216-368-8919; E-mail: dxd49{at}po.cwru.edu.

Key Words: AR • Androgen • TβRII • Prostate • Cancer • Smad • Smad3 • tumor suppressor • apoptosis • cyclin D

The androgen receptor cross-talks with transforming growth factor-β (TGF-β) through mechanisms that remain poorly understood. Here we provide strong evidence that 5-dihydrotestosterone (DHT) intercepts the ability of prostate epithelial cells to undergo TGF-β–induced apoptosis, and present a new model for this androgenic effect. We report that DHT decreases the level of TGF-β receptor II (TβRII) through a transcriptional mechanism, leading to suppression of the ability of TGF-β to down-regulate expression of Bcl-xL and cyclin Ds, activate caspase-3, and induce apoptosis. Promoter analysis, DNA pulldown, and electrophoretic mobility shift assays support that transcriptional down-regulation of TβRII by DHT occurs through Sp1/Sp3 response elements, with the binding of Sp1 to the TβRII promoter being suppressed by DHT, largely driven by loss of Sp1 protein and/or activity. These results provide fresh insight on the mechanism of growth control by androgens and the progression of prostate cancer to androgen independence. [Cancer Res 2008;68(19):8173–82]

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