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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression

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

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

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. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients.

Methods

We 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.

Results

The 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).

Conclusions

Our 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.
Literature
1.
2.
Mitsiades N. A road map to comprehensive androgen receptor axis targeting for castration-resistant prostate cancer. Cancer Res. 2013;73(15):4599–605.CrossRefPubMed
3.
Hara N, Nishiyama T. Androgen metabolic pathway involved in current and emerging treatment for men with castration resistant prostate cancer: intraprostatic androgens as therapeutic targets and endocrinological biomarkers. Curr Drug Targets. 2014;15(13):1215–24.CrossRefPubMed
4.
Mitsiades N, Sung CC, Schultz N, Danila DC, He B, Eedunuri VK, Fleisher M, Sander C, Sawyers CL, Scher HI. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors. Cancer Res. 2012;72(23):6142–52.CrossRefPubMedPubMedCentral
5.
Tamae D, Byrns M, Marck B, Mostaghel EA, Nelson PS, Lange P, Lin D, Taplin ME, Balk S, Ellis W, et al. Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum. J Steroid Biochem Mol Biol. 2013;138:281–9.CrossRefPubMed
6.
Bambury RM, Rathkopf DE. Novel and next-generation androgen receptor-directed therapies for prostate cancer: beyond abiraterone and enzalutamide. Urol Oncol. 2015;34(8):348–55.
7.
Santer FR, Erb HH, McNeill RV. Therapy escape mechanisms in the malignant prostate. Semin Cancer Biol. 2015;35:133–44.
8.
Mitra R, Goodman OB Jr. CYP3A5 regulates prostate cancer cell growth by facilitating nuclear translocation of AR. Prostate. 2015;75(5):527–38.CrossRefPubMed
9.
Levesque E, Laverdiere I, Lacombe L, Caron P, Rouleau M, Turcotte V, Tetu B, Fradet Y, Guillemette C. Importance of 5alpha-reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer. Clin Cancer Res. 2014;20(3):576–84.CrossRefPubMed
10.
Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 2009;73(5 Suppl):S4–10.CrossRefPubMed
11.
Titus MA, Li Y, Kozyreva OG, Maher V, Godoy A, Smith GJ, Mohler JL. 5alpha-reductase type 3 enzyme in benign and malignant prostate. Prostate. 2014;74(3):235–49.CrossRefPubMed
12.
Taplin ME, Manola J, Oh WK, Kantoff PW, Bubley GJ, Smith M, Barb D, Mantzoros C, Gelmann EP, Balk SP. A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU Int. 2008;101(9):1084–9.CrossRefPubMed
13.
Rowland A, Miners JO, Mackenzie PI. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol. 2013;45(6):1121–32.CrossRefPubMed
14.
Dutton GJ. Developmental aspects of drug conjugation, with special reference to glucuronidation. Annu Rev Pharmacol Toxicol. 1978;18:17–35.CrossRefPubMed
15.
Guillemette C, Levesque E, Harvey M, Bellemare J, Menard V. UGT genomic diversity: beyond gene duplication. Drug Metab Rev. 2010;42(1):24–44.CrossRefPubMed
16.
Turgeon D, Carrier JS, Levesque E, Beatty BG, Belanger A, Hum DW. Isolation and characterization of the human UGT2B15 gene, localized within a cluster of UGT2B genes and pseudogenes on chromosome 4. J Mol Biol. 2000;295(3):489–504.CrossRefPubMed
17.
Turgeon D, Carrier JS, Levesque E, Hum DW, Belanger A. Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members. Endocrinology. 2001;142(2):778–87.CrossRefPubMed
18.
Chouinard S, Pelletier G, Belanger A, Barbier O. Cellular specific expression of the androgen-conjugating enzymes UGT2B15 and UGT2B17 in the human prostate epithelium. Endocr Res. 2004;30(4):717–25.CrossRefPubMed
19.
Chouinard S, Yueh MF, Tukey RH, Giton F, Fiet J, Pelletier G, Barbier O, Belanger A. Inactivation by UDP-glucuronosyltransferase enzymes: the end of androgen signaling. J Steroid Biochem Mol Biol. 2008;109(3-5):247–53.CrossRefPubMed
20.
Levesque E, Turgeon D, Carrier JS, Montminy V, Beaulieu M, Belanger A. Isolation and characterization of the UGT2B28 cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase. Biochemistry. 2001;40(13):3869–81.CrossRefPubMed
21.
Belledant A, Hovington H, Garcia L, Caron P, Brisson H, Villeneuve L, Simonyan D, Tetu B, Fradet Y, Lacombe L, et al. The UGT2B28 sex-steroid inactivation pathway is a regulator of Steroidogenesis and modifies the risk of prostate cancer progression. Eur Urol. 2015;69(4):601–9.
22.
Grosse L, Paquet S, Caron P, Fazli L, Rennie PS, Belanger A, Barbier O. Androgen glucuronidation: an unexpected target for androgen deprivation therapy, with prognosis and diagnostic implications. Cancer Res. 2013;73(23):6963–71.CrossRefPubMed
23.
Chouinard S, Barbier O, Belanger A. UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 enzymes are major determinants of the androgen response in prostate cancer LNCaP cells. J Biol Chem. 2007;282(46):33466–74.CrossRefPubMed
24.
Nadeau G, Bellemare J, Audet-Walsh E, Flageole C, Huang SP, Bao BY, Douville P, Caron P, Fradet Y, Lacombe L, et al. Deletions of the androgen-metabolizing UGT2B genes have an effect on circulating steroid levels and biochemical recurrence after radical prostatectomy in localized prostate cancer. J Clin Endocrinol Metab. 2011;96(9):E1550–7.CrossRefPubMed
25.
Laverdiere I, Flageole C, Audet-Walsh E, Caron P, Fradet Y, Lacombe L, Levesque E, Guillemette C. The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy. Endocr Relat Cancer. 2015;22(1):77–85.CrossRefPubMed
26.
Williamson SC, Mitter R, Hepburn AC, Wilson L, Mantilla A, Leung HY, Robson CN, Heer R. Characterisations of human prostate stem cells reveal deficiency in class I UGT enzymes as a novel mechanism for castration-resistant prostate cancer. Br J Cancer. 2013;109(4):950–6.CrossRefPubMedPubMedCentral
27.
Zhang A, Zhang J, Plymate S, Mostaghel EA. Classical and non-classical roles for pre-receptor control of DHT metabolism in prostate cancer progression. Horm Cancer. 2016;7(2):104–13.CrossRefPubMedPubMedCentral
28.
Hu DG, Mackenzie PI, McKinnon RA, Meech R. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metab Rev. 2016;48(1):47–69.CrossRefPubMed
Metadata
Title
UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression
Authors
Delores J. Grant
Zinan Chen
Lauren E. Howard
Emily Wiggins
Amanda De Hoedt
Adriana C. Vidal
Skyla T. Carney
Jill Squires
Clara E. Magyar
Jiaoti Huang
Stephen J. Freedland
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3463-6

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