title: The UGT2B28 Sex-steroid Inactivation Pathway Is a Regulator of Steroidogenesis and Modifies the Risk of Prostate Cancer Progression.
abstract: BACKGROUND
  Androgen inactivation occurs mainly through the glucuronidation conjugative reaction mediated by UDP-glucuronosyltransferases (UGTs). This metabolic process is involved in the control of systemic and local androgen bioavailability.
  
  
  OBJECTIVE
  To examine the relationship among expression of the androgen-inactivating UGT2B28 enzyme, circulating steroid hormone levels, and clinical phenotype in prostate cancer (PCa).
  
  
  METHODS
  We conducted an analysis of a high-density prostate tumor tissue microarray consisting of 239 localized PCa cases. The study of 51 additional PCa patients with no copies of UDP glucuronosyltransferase 2B subfamily, polypeptide B28 (UGT2B28) in their genomes was performed to confirm the importance of the enzyme on circulating hormone levels.
  
  
  METHODS
  Steroid hormones were measured by mass spectrometry. Multivariate Cox proportional hazard models assessed the influence of UGT2B28 on progression, and general linear model regression evaluated variations in hormone levels.
  
  
  CONCLUSIONS
  Tumor overexpression of UGT2B28 was associated with lower prostate-specific antigen levels at diagnosis, higher Gleason scores, margin and nodal invasion status, and it was shown to be an independent prognostic factor associated with progression. Enzyme overexpression correlated with 30% higher circulating levels of testosterone (T) and dihydrotestosterone (DHT). Patients with no copies of UGT2B28 in their genomes have lower levels of T (19%), DHT (17%), its glucuronide metabolites (18-38%), and enhanced levels of the adrenal precursor androstenedione (36%).
  
  
  CONCLUSIONS
  The UGT2B28 steroid-inactivating pathway modifies circulating T and DHT levels, and UGT2B28 overexpression is associated with high-grade PCa. Our work has uncovered the role of UGT2B28 as a regulator of steroidogenesis and underscores the interconnectivity among the steroid-inactivation capacity of cancer cells, hormone levels, disease characteristics, and the risk of cancer progression.
  
  
  RESULTS
  The androgen-inactivating UGT2B28 enzyme influences hormone levels, clinical and pathologic factors, and the risk of cancer progression.
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Belledant
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Hovington
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Luciana
authors.initials: L
authors.lastname: Garcia
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Hervé
authors.initials: H
authors.lastname: Brisson
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Lyne
authors.initials: L
authors.lastname: Villeneuve
authors.affiliation: Clinical and Evaluative Research Platform, Centre Hospitalier Universitaire de Québec Research Center, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Simonyan
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Têtu
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center, Faculty of Medicine, Laval University, Québec, Canada. Electronic address: eric.levesque@crchuq.ulaval.ca.
authors.forename: Eric
authors.initials: E
authors.lastname: Lévesque
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D001706:Biopsy; D013196:Dihydrotestosterone / Q000097:blood; D018450:Disease Progression; D008401:Gas Chromatography-Mass Spectrometry; D020022:Genetic Predisposition to Disease; D020719:Glucuronides / Q000097:blood; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007610:Kallikreins / Q000097:blood; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D053719:Tandem Mass Spectrometry; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D020719:Glucuronides; D013196:Dihydrotestosterone; D013739:Testosterone; C428927:UDP-glucuronosyltransferase, UGT2B28; D014453:Glucuronosyltransferase; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Circulating hormone levels; Disease aggressiveness; Prostate cancer prognosis; Steroid metabolism; UDP-glucuronosyltransferase