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Title: Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer.
Epworth Authors: Costello, Anthony
Hovens, Christopher
Corcoran, Niall
Other Authors: Fankhauser, Matthew
Tan, Yuen
Macintyre, Geoff
Haviv, Izhak
Hong, Matthew
Nguyen, Anne
Pedersen, John
Keywords: Canonical Androstenedione Reduction
Signaling Androgens
Hormone-Refractory Prostate Cancer
Prostate Cancer
Hormone-Naïve Prostate Cancer
Prostatic Neoplasms
Androgen Receptors
Hydroxyprostaglandin Dehydrogenases
Signal Transduction
Australian Prostate Cancer Research Centre Epworth HealthCare, Melbourne, Victoria, Australia
Issue Date: Nov-2014
Publisher: American Association for Cancer Research
Citation: Clin Cancer Res. 2014 Nov 1;20(21):5547-57
Abstract: PURPOSE: It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression. EXPERIMENTAL DESIGN: Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset. RESULTS: Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-α dione" pathway.
DOI: 10.1158/1078-0432.CCR-13-3483
PubMed URL:
ISSN: 1078-0432
Journal Title: Clinical Cancer Research
Type: Journal Article
Affiliated Organisations: TissuPath Specialist Pathology, Mount Waverley
NICTA Victoria Research Laboratory, University of Melbourne, Parkville
The Faculty of Medicine, Monash University, Melbourne
Departments of Urology and Surgery, Royal Melbourne Hospital
Type of Clinical Study or Trial: Predictive Value of Tests
Appears in Collections:Cancer Services
UroRenal, Vascular
Epworth Prostate Centre

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