UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression

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.

Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression

“…17,29,31,33,50,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] The expression of UGTs is repressed in certain tumour types relative to their normal tissue counterparts, but remarkably enhanced in other cancers, such as those of the prostate, pancreas, lung, endometrium and in CLL, indicating diverse patterns of regulation of UGT expression in tumours. 17,29,31,33,50,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] These perturbed levels of UGTs are consistent with altered metabolic functions in tumours and suggest that UGTs might influence cancer progression, independent of exposure to therapeutic drugs (Table 1). Notably, in recent reports investigating metabolic perturbations present in the transcriptome and metabolome of multiple tumour types, 7...…”

“…4). 53,58,60,62,[75][76][77] A 2013 meta-analysis established that germline UGT2B17 deletion (inherited deficiency) is associated with an increased risk of prostate cancer. 78 Such data are lacking for the less common UGT2B28 deletion polymorphism.…”

“…expression (n = 190) Higher expression linked to higher risk of biochemical recurrence after prostatectomy58 UGT2B17RNA and protein expression (n = 287) Higher expression linked to higher Gleason score and risk of castration-resistant prostate cancer60 UGT2B17 Protein expression (n = 239) Higher expression linked to recurrence after prostatectomy and risk of metastasis 59 Bladder UGT1A RNA and protein expression (n = 145) Lower expression linked to recurrence/progression Inverse correlation with tumour grade/stage 31 Breast UGT2B15 UGT2B17 RNA expression (n = 2000) Lower expression in higher tumour grade Expression associated with survival in distinct subgroups 55 UGT8 RNA expression (n = 744) Higher expression linked to the risk of metastasis to the lung b 68 UGT8 RNA (n = 761) and protein (n = 40) expressionHigher expression linked to shorter lung-metastasis-free survival65 Head and neck UGT2B17 DNA variations (n = 234) Germline deletion combined with TP53 mutations in primary tumours increases risk of relapse after surgery 99 a RNA expression was assessed by microarray or reverse transcription-quantitative PCR. Protein expression was assessed by immunohistochemistry.…”

Host factors influence Barrett’s carcinogenesis: findings from a mouse gastroduodenal reflux model

“…It has been confirmed that UGT is present in not only the liver, but also the small intestine, kidneys, brain, and esophagus [21, 22]. UGT2B is present in esophageal squamous cell carcinoma, with some recent reports indicating that it is related to prostate cancer and UGT2B genetic polymorphisms [23, 24]. Accordingly, genetic polymorphisms between UGT2B specimens might also be actively involved in the metabolism of carcinogens in the digestive tract.…”

Normalized Testosterone Glucuronide as a Potential Urinary Biomarker for Highly Variable UGT2B17 in Children 7–18 Years

“…Absence of UGT2B17 gene (CNV = 0) seems to increase the risk of cancer for prostate, breast, pancreatic, and lung cancer, but decreases the risk of colorectal cancer . On the other hand, overexpression of UGT2B17 protein has been linked to biochemical recurrence of prostate cancer, expedition in progression to castration‐resistant prostate cancer, and poorer prognosis in chronic lymphocytic leukemia due to inactivation of protective prostaglandin E 2 . Although presence of the UGT2B17 gene may be oncoprotective, its seemingly deleterious role in cancer progression suggests a separate function that is under differential regulation.…”