The majority of patients treated with ADT, which suppress androgen production or androgen receptor activity, show clinical improvement. Unfortunately, many patients relapse with a more aggressive form of prostate cancer termed castration-resistant prostate cancer. Several mechanisms have been proposed for explaining the development of CRPC. The AR gene is amplified in about one third of cases. Alteration of transcriptional coactivators and activation of signal pathways may enhance AR responses to low levels of androgens. AR mutations in CRPC allow the receptor to be activated by weak androgens, other steroid hormones, or drugs. In addition, direct measurements of intraprostatic androgens in castrated men with CRPC have shown that the levels are not significantly reduced compared with normal prostate, indicating that cancer cells generate significant active intracellular hormone levels to fuel their own growth. Based on the above findings, genetic variants in genes of sex hormone metabolic pathways have been investigated as candidates for prostate cancer risk in many association studies. However, few studies have examined the association of these polymorphisms with prostate cancer progression and survival. Indeed, studies have shown the impact of variations in CYP19A1, HSD3B1, HSD17B4, SLCO2B1, and SLCO1B3 on time to progression during ADT, but there is still a lack of markers better defining lethal prostate cancer. In the present study, we sought to investigate the prognostic significance of common variants in sex hormone pathway genes on disease progression, prostate cancer-specific mortality, and all-cause mortality in a cohort of 645 prostate cancer patients receiving ADT. We have identified two genetic polymorphisms, rs12529 in AKR1C3 and CAG repeat in AR, retained their associations with PCSM after ADT while controlling for known prognostic factors, age at diagnosis, clinical stage, Gleason score, PSA level at ADT initiation, PSA nadir, and time to PSA nadir, suggesting that these host genetic factors add information above and beyond currently used predictors. Intriguingly, patients possessing a greater number of unfavorable alleles had a shorter survival following ADT. A critical step in the synthesis of AR ligands involves the conversion of androstenedione to testosterone, which is catalyzed by 17b-hydroxysteroid dehydrogenases type 3 and type 5, also called aldo-keto reductase 1C3. HSD17B3 is the predominant enzyme in catalyzing testosterone formation in testis, but synthesis of active androgens proceeds via AKR1C3 in prostate. Several studies indicate that AKR1C3 is over-expressed in prostate cancer and its expression increases with the disease progression. AKR1C3 has also been suggested to contribute to the development of CRPC through the intratumoral formation of the active androgens. Therefore, a specific inhibitor of AKR1C3 might have the potential to impact both hormone-sensitive prostate cancer and CRPC. Although the nonsynonymous polymorphism rs12529 causes a histidine to glutamine substitution at position 5 of AKR1C3, the amino acid is replaced by an amino acid of very similar chemical properties, leading to a conservative change. Nonetheless, rs12529 alters a putative exonic splicing enhancer motif that may cause alternative splicing regulatory effects, according to the prediction of FASTSNP. Alternative splicing of AKR1C3 might regulate gene function and influence the efficacy of ADT. Moreover, AKR1C3 rs12529 has also been associated with lung and bladder cancer risk.
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