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Transcript Profiling of the Androgen Signal in Normal Prostate, Benign Prostatic Hyperplasia, and Prostate Cancer

Department of Pharmacology (D.R.B., S.S., T.M.P.), Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084; and Department of Urology (D.M.P.), Stanford University School of Medicine, Stanford, California 94305

Address all correspondence and requests for reprints to: Trevor M. Penning, Department of Pharmacology, University of Pennsylvania School of Medicine, 130C John Morgan Building, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104-6084. E-mail: penning{at}pharm.med.upenn.edu

Human prostate adenocarcinoma (CaP) and benign prostatic hyperplasia (BPH) have epithelial and stromal cell origins, respectively. To determine whether the androgen signal is processed differently in these cell types the expression of transcripts for enzymes that control ligand access to the androgen receptor (AR) were measured. Transcripts for type 2 5-reductase, ketosteroid reductases [aldo-keto reductase (AKR)1C1-AKR1C4], the major oxidative 3-hydroxysteroid dehydrogenase (HSD) retinol dehydrogenase (RODH)-like 3-HSD (RL-HSD) and nuclear receptors [AR, estrogen receptor (ER), and ERß] were determined in whole human prostate and in cultures of primary epithelial cells (PEC) and primary stromal cells (PSC) from normal prostate, CaP and BPH by real-time RT-PCR. Normal PEC (n = 14) had higher levels of AKR1C1 (10-fold, P < 0.001), AKR1C2 (115-fold, P < 0.001) and AKR1C3 (6-fold, P < 0.001) than normal PSC (n = 15), suggesting that reductive androgen metabolism occurs. By contrast, normal PSC had higher levels of AR (8-fold, P < 0.001) and RL-HSD (21-fold, P < 0.001) than normal PEC, suggesting that 3-androstanediol is converted to 5-dihydrotestosterone to activate AR. In CaP PEC (n = 14), no significant changes in transcript levels vs. normal PEC were observed. In BPH PSC (n = 21) transcripts for AR (2-fold, P < 0.001), AKR1C1 (4-fold, P < 0.001), AKR1C2 (10-fold P < 0.001), AKR1C3 (4-fold, P < 0.001) and RL-HSD (3-fold, P < 0.003) were elevated to increase androgen response. Differences in the AR:ERß transcript ratios (eight in normal PEC vs. 280 in normal PSC) were maintained in PEC and PSC in diseased prostate. These data suggest that CaP may be more responsive to an ERß agonist and BPH may be more responsive to androgen ablation.

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