UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression

Delores J Grant,Skyla T Carney,Adriana C Vidal,Jiaoti Huang,Amanda De Hoedt,Clara E Magyar,Lauren E Howard,Jill Squires,Emily Wiggins,Stephen J Freedland,Zinan Chen

doi:10.1186/s12885-017-3463-6

Abstract

BackgroundUridine 5′-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients.MethodsWe determined the expression of UGT2B15, UGT2B17, and UGT2B28 enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each protein’s percent positive and H-score, a weighted score of staining intensity, and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were divided at the median and we tested the association between UGT2B17 group and risk of BCR.ResultsThe median follow-up for all patients was 118 months (IQR: 85-144). Of 190, 83 (44%) patients developed BCR. We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend for an association between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found that patients with UGT2B17 higher levels of expression had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041), although this association was attenuated in the multivariable model (HR = 1.50, 95% CI 0.94-2.40, p = 0.088).ConclusionsOur findings suggest that UGT2B17 overexpression may be associated with a significant increased risk of BCR. These results are consistent with previous reports which showed UGT2B17 significantly expressed in advanced prostate cancer including prostate tumor metastases.

Highlights

Uridine 5′-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue
Recent evidence suggests that steroideogenic enzymes responsible for the catabolism of intraprostatic testosterone metabolites may be linked to biochemical recurrence (BCR) and tumor progression to castration-resistant prostate cancer (CRPC), those associations are less understood [2, 7,8,9,10,11,12]
The median percentage of cells staining positive for UGT2B15, UGT2B17, and UGT2B28 was 39%, 74%, and 77% respectively

Summary

Introduction

Uridine 5′-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. Enzymes UGT2B15 and UGT2B17 exhibit substrate specificity for androgens such as testosterone, dihydrotestosterone (DHT), DHT metabolites, androsterone and 5α-androstane3α,17β-diol [16, 17]. Those enzymes conjugate androgens present in the lumen and basal epithelial tissue of the prostate [18, 19]. The UGT2B28 enzymes have been shown to be expressed in human testis, prostate, and prostate cancer cell line, LNCaP, where they conjugate 5α-androstane-3α,17β-diol, 5βandrostane-3α,17β-diol and androsterone, and testosterone [20] (Fig. 1). The expression levels of UGT2B17, B15, and B28 may be predictors of intraprostatic levels of androgens and prostate cancer phenotype

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Conclusion