Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC.
Departments of Urology and Surgery, Royal Melbourne Hospital;
Matthew
M
Fankhauser
Departments of Urology and Surgery, Royal Melbourne Hospital;
Yuen
Y
Tan
NICTA Victoria Research Laboratory, University of Melbourne, Parkville;
Geoff
G
Macintyre
NICTA Victoria Research Laboratory, University of Melbourne, Parkville;
Izhak
I
Haviv
Departments of Urology and Surgery, Royal Melbourne Hospital;
Matthew K H
MK
Hong
Departments of Urology and Surgery, Royal Melbourne Hospital;
Anne
A
Nguyen
TissuPath Specialist Pathology, Mount Waverley; The Faculty of Medicine, Monash University, Melbourne; and.
John S
JS
Pedersen
Departments of Urology and Surgery, Royal Melbourne Hospital; Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia.
Anthony J
AJ
Costello
Departments of Urology and Surgery, Royal Melbourne Hospital; Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia.
Christopher M
CM
Hovens
Departments of Urology and Surgery, Royal Melbourne Hospital; Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia niallmcorcoran@gmail.com.
Niall M
NM
Corcoran
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000728:Androgens / Q000378:metabolism*; D000735:Androstenedione / Q000378:metabolism*; D004960:Estradiol Dehydrogenases / Q000378:metabolism; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
C410798:AR protein, human; D000728:Androgens; D011944:Receptors, Androgen; D000735:Androstenedione; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D004960:Estradiol Dehydrogenases