title: Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer.
abstract: Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.
authors.affiliation: Departments of Internal Medicine, Urology, and Pathology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. j.hofland@erasmusmc.nl
authors.forename: Johannes
authors.initials: J
authors.lastname: Hofland
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
authors.forename: Natasja F J
authors.initials: NF
authors.lastname: Dits
authors.forename: Jacobie
authors.initials: J
authors.lastname: Steenbergen
authors.forename: Geert J L H
authors.initials: GJ
authors.lastname: van Leenders
authors.forename: Guido
authors.initials: G
authors.lastname: Jenster
authors.forename: Fritz H
authors.initials: FH
authors.lastname: Schröder
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics* / 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; D000818:Animals; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009919:Orchiectomy; D011284:Pregnenolone / Q000378:metabolism; D011375:Progesterone Reductase / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000728:Androgens; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D011284:Pregnenolone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; D011375:Progesterone Reductase; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C476566:steroid-5alpha-reductase type 1