Abstract
Polymorphisms in the genes SRD5A1 and SRD5A2 encoding androgen biosynthetic 5α-reductase enzymes have been associated with an altered risk of biochemical recurrence after radical prostatectomy in localized prostate cancer. 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. 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-3α, 17β-diol-17-glucuronide (3α-diol-17G) levels as opposed to lower levels of both 3α-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 3α-diol-3G. The SRD5A2 rs676033 variant further correlated with enhanced intraprostatic exposure to 5α-reduced steroids (dihydrotestosterone and its metabolite 3β-diol). Similarly, the SRD5A1 rs166050C risk variant was associated with greater prostatic exposure to androsterone, whereas no association was noted with circulating steroids. Our data support the association of 5α-reductase germline polymorphisms with the hormonal milieu in patients with prostate cancer. Further studies are needed to evaluate if these variants influence 5α-reductase inhibitor efficacy.
Highlights
Prostate cancer is the most frequent malignancy in men and the second leading cause of cancer death in Western countries [1]
It is well established that androgens play a central role in prostate cancer progression even until it reaches advanced stages
The importance of androgens in early cancer initiation is emphasized by the fact that finasteride, a 5-AR type 2 inhibitor, and dutasteride, a dual 5-AR inhibitor targeting both 5-AR type 1 and type 2 enzymes, have been shown to reduce by almost 23% the risk of prostate cancer incidence [5, 6]
Summary
Prostate cancer is the most frequent malignancy in men and the second leading cause of cancer death in Western countries [1]. It is well established that androgens play a central role in prostate cancer progression even until it reaches advanced stages. The balance in expression of these genes shifts toward predominant expression of SRD5A1 [3, 4], supporting a role for both enzymes in DHT bioavailability and carcinogenesis. 5-AR enzymes represent attractive targets for preventing prostate cancer development. The importance of androgens in early cancer initiation is emphasized by the fact that finasteride, a 5-AR type 2 inhibitor, and dutasteride, a dual 5-AR inhibitor targeting both 5-AR type 1 and type 2 enzymes, have been shown to reduce by almost 23% the risk of prostate cancer incidence [5, 6]. The REDEEM trial conducted with patients with low-risk prostate cancer showed that dutasteride reduced by 10% the likelihood of cancer progression [7]
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