Importance of 5α-Reductase Gene Polymorphisms on Circulating and Intraprostatic Androgens in Prostate Cancer

被引:23
|
作者
Levesque, Eric [1 ,2 ,3 ,4 ]
Laverdiere, Isabelle [1 ,2 ]
Lacombe, Louis [3 ,4 ]
Caron, Patrick [1 ,2 ]
Rouleau, Melanie [1 ,2 ]
Turcotte, Veronique [1 ,2 ]
Tetu, Bernard [3 ,4 ]
Fradet, Yves [3 ,4 ]
Guillemette, Chantal [1 ,2 ,3 ]
机构
[1] CHU Quebec, Pharmacogen Lab, Res Ctr, Quebec City, PQ G1V 4G2, Canada
[2] Fac Pharm, Quebec City, PQ, Canada
[3] CHU Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada
[4] Univ Laval, Fac Med, Quebec City, PQ G1K 7P4, Canada
关键词
STEROID-HORMONES; SRD5A2; GENE; RISK; EXPRESSION; ESTROGEN; TESTOSTERONE; DUTASTERIDE; ASSOCIATION; ENZYMES; MARKERS;
D O I
10.1158/1078-0432.CCR-13-1100
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Polymorphisms in the genes SRD5A1 and SRD5A2 encoding androgen biosynthetic 5 alpha-reductase enzymes have been associated with an altered risk of biochemical recurrence after radical prostatectomy in localized prostate cancer. Experimental Design: To gain potential insights into SRD5A biologic effects, we examined the relationship between SRD5A prognostic markers and endogenous sex-steroid levels measured by mass spectrometry in plasma samples and corresponding prostatic tissues of patients with prostate cancer. Results: We report that five of the seven SRD5A markers differentially affect sex-steroid profiles of dihydrotestosterone and its metabolites in both the circulation and prostatic tissues of patients with prostate cancer. Remarkably, a 32% increase in intraprostatic testosterone levels was observed in the presence of the high-risk SRD5A rs2208532 polymorphism. Moreover, SRD5A2 markers were associated predominantly with circulating levels of inactive glucuronides. Indeed, the rs12470143 SRD5A2 protective allele was associated with high circulating androstane-3 alpha, 17 beta-diol-17-glucuronide (3 alpha-diol-17G) levels as opposed to lower levels of both 3 alpha-diol-17G and androsterone-glucuronide observed with the rs2208532 SRD5A2 risk allele. Moreover, SRD5A2 rs676033 and rs523349 (V89L) risk variants, in strong linkage disequilibrium, were associated with higher circulating levels of 3 alpha-diol-3G. The SRD5A2 rs676033 variant further correlated with enhanced intraprostatic exposure to 5 alpha-reduced steroids (dihydrotestosterone and its metabolite 3 beta-diol). Similarly, the SRD5A1 rs166050C risk variant was associated with greater prostatic exposure to androsterone, whereas no association was noted with circulating steroids. Conclusions: Our data support the association of 5 alpha-reductase germline polymorphisms with the hormonal milieu in patients with prostate cancer. Further studies are needed to evaluate if these variants influence 5 alpha-reductase inhibitor efficacy. (C) 2013 AACR.
引用
收藏
页码:576 / 584
页数:9
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