Dataset Information

Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention.

ABSTRACT: Inhibitors of 5alpha-reductase (SRD5A) that lower intraprostatic levels of dihydrotestosterone (DHT) reduce the overall incidence of prostate cancer (PCa), but there is significant variation in chemopreventive activity between individual men. In seeking molecular alterations that might underlie this variation, we compared gene expression patterns in patients with localized PCa who were randomized to prostatectomy alone versus treatment with two different doses of the SRD5A inhibitor dutasteride. Prostatic levels of DHT were decreased by >90% in both dutasteride-treated patient groups versus the untreated patient group. Despite significant and uniform suppression of tissue DHT, unsupervised clustering based on prostatic gene expression did not discriminate these groups. However, subjects could be resolved into distinct cohorts characterized by high or low expression of genes regulated by the androgen receptor (AR), based solely on AR transcript expression. The higher-dose dutasteride treatment group was found to include significantly fewer cancers with TMPRSS2-ERG genetic fusions. Dutasteride treatment was associated with highly variable alterations in benign epithelial gene expression. Segregating subjects based on expression of AR and androgen-regulated genes revealed that patients are differentially sensitive to SRD5A inhibition. Our findings suggest that AR levels may predict the chemopreventive efficacy of SRD5A inhibitors.

SUBMITTER: Mostaghel EA

PROVIDER: S-EPMC2822890 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention.

Mostaghel Elahe A EA Geng Linda L Holcomb Ilona I Coleman Ilsa M IM Lucas Jared J True Lawrence D LD Nelson Peter S PS

Cancer research 20100202 4

Inhibitors of 5alpha-reductase (SRD5A) that lower intraprostatic levels of dihydrotestosterone (DHT) reduce the overall incidence of prostate cancer (PCa), but there is significant variation in chemopreventive activity between individual men. In seeking molecular alterations that might underlie this variation, we compared gene expression patterns in patients with localized PCa who were randomized to prostatectomy alone versus treatment with two different doses of the SRD5A inhibitor dutasteride. ...[more]

PMID: 20124490

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Project description:The progression of castration resistant prostate cancer (CRPC) is driven by the intratumoral conversion of adrenal androgen precursors to potent androgens. The expression of aldo-keto reductase 1C3 (AKR1C3), which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. The oxidation of androgens to their inactive form is catalysed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2), but little attention is given to the expression levels of this enzyme. In this study, we show that the 11-oxygenated androgen precursors of adrenal origin are the preferred substrate for AKR1C3. In particular we show that the enzymatic efficiency of AKR1C3 is 8- and 24-fold greater for 11-ketoandrostenedione than for the classic substrates androstenedione and 5α-androstanedione, respectively. Using three independent experimental systems and a computational model we subsequently show that increased ratios of AKR1C3:17βHSD2 significantly favours the flux through the 11-oxygenated androgen pathway as compared to the classical or 5α-androstanedione pathways. Our findings reveal that the flux through the classical and 5α-androstanedione pathways are limited by the low catalytic efficiently of AKR1C3 towards classical androgens combined with the high catalytic efficiency of 17βHSD2, and that the expression of the oxidative enzyme therefore plays a vital role in determining the steady state concentration of active androgens. Using microarray data from prostate tissue we confirm that the AKR1C3:17βHSD2 ratio is significantly increased in patients undergoing androgen deprivation therapy as compared to benign tissue, and further increased in patients with CRPC. Taken together this study therefore demonstrates that the ratio of AKR1C3:17βHSD2 is more important than AKR1C3 expression alone in determining intratumoral androgen levels and that 11-oxygenated androgens may play a bigger role in CRPC than previously anticipated.

Project description:Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with restoration of sensitivity to subsequent AR inhibitor therapies.

Dataset Information

Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention.

Publications

Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention.

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