Correlation between circulatory, local prostatic, and intra‐prostatic androgen levels

Olsson, Mats Joakim Robert; Ekström, Lena; Guillemette, Chantal; Bélanger, Alain; Rane, Anders; Gustafsson, Ove

doi:10.1002/pros.21307

Cited by 28 publications

(23 citation statements)

References 18 publications

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“…It is therefore tempting to speculate that the loss of this induction is likely involved in the phenotypic changes allowing tumor cells to proliferate in the presence of low androgen levels, as observed in CRPCs (8). This idea is supported by the inverse relationship existing between UGT2B15 and UGT2B17 expression and androgen-dependent prostate cancer cell proliferation (14) and by the strong influence that UGT2B15 and UGT2B17 polymorphisms exert on tissue androgen levels (36). The loss of UGT genes' sensitivity may allow prostate cancer cells to maintain sufficient DHT levels to activate AR and its regulated genes in CRPCs (37,38).…”

Section: Discussionmentioning

confidence: 99%

Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

et al. 2013

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Androgen deprivation therapy (ADTh) remains a mainstay of prostate cancer treatment, but its efficacy is bypassed by mechanisms that are not fully understood. In human prostate cancer cells, androgen glucuronidation, catalyzed by the two UDP-glucuronosyltransferase (UGT) enzymes UGT2B15 and UGT2B17, is the major androgen inactivation pathway. In this study, we investigated the effect of ADTh on androgen glucuronidation to evaluate its potential clinical utility for prostate cancer prognosis or therapy. UGT2B15 and UGT2B17 expression was evaluated in prostate cancer specimens from untreated or treated patients and in cell models of prostate cancer exposed to clinically relevant antiandrogens. UGT2B15 and UGT2B17 protein levels in prostate were increased after 5 months of ADTh when compared with specimens from untreated patients. UGT2B15 expression remained elevated for up to 12 months, but UGT2B17 returned to initial levels as soon as after 6 months. Several androgen receptor (AR) antagonists tested caused a dose-and time-dependent stimulation of UGT2B15 and UGT2B17 expression and androgen glucuronidation in prostate cancer cell lines. The role of AR in these regulatory events was confirmed using AR-deficient LNCaP cells, in which UGT2B attenuation reduced the antiproliferative effects of AR pharmacologic antagonists. Through this combination of clinical and functional investigations, our work revealed that ADTh stimulates a local androgen metabolism in prostate cells, establishing a foundation to evaluate the potential of UGT2B15 and UGT2B17 as drug targets and/or molecular markers for ADTh responsiveness and maintenance in prostate cancer. Cancer Res; 73(23); 6963-71. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

et al. 2013

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“…Other studies showed that UGT2B17 CNV was associated with AAG levels in subjects of European descent. Olsson et al (2011) showed that AAG levels were significantly associated with the UGT2B17 CNV, suggesting that the UGT2B17 CNV genotypes are significantly associated with AAG levels. Thus, the relationship we observed between UGT2B17 CNV and AAG levels in Whites is consistent with the two previous reports.…”

Section: Ugt2b Variants: Aag Levels and Prostate Cancer Riskmentioning

confidence: 95%

“…In addition, a polymorphism in the regulatory region of the UGT2B17 gene has been associated with altered levels of AAG (Hu et al, 2010). While both the UGT2B17 and UGT2B15 polymorphisms are significantly associated with AAG levels in European populations, no observations have been made in individuals of African descent (Hsing, 2001;Swanson et al, 2007;Olsson et al, 2011).…”

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confidence: 99%

Association of Uridine Diphosphate-Glucuronosyltransferase 2B Gene Variants with Serum Glucuronide Levels and Prostate Cancer Risk

Grant

Hoyo

Oliver

et al. 2013

Genetic Testing and Molecular Biomarkers

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Aims: Uridine diphosphate-glucuronosyltransferase 2B (UGT2B) enzymes conjugate testosterone metabolites to enable their excretion in humans. The functional significance of the UGT2B genetic variants has never been described in humans. We evaluated UGT2B variants in relation to plasma androstane-3a,17b-diol-glucuronide (AAG) levels and the prostate cancer risk. Results: AAG levels were measured in sera from 150 controls and compared to the polymorphisms of UGT2B17, UGT2B15, and UGT2B7. Genomic DNA from controls (301) and cases (148) was genotyped for the polymorphisms, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analyses. Having two copies of UGT2B17 was associated with higher AAG levels in controls among Whites ( p = 0.02), but not Blacks ( p = 0.82). Logistic regression models adjusting for age and race revealed that homozygosity for the G allele of the UGT2B15 D85Y polymorphism was directly associated with the prostate cancer risk (OR = 2.70, 95% CI = 1.28, 5.55). Conclusions: While the small sample size limits inference, our findings suggest that an association between the UGT2B17 copy number variant (CNV) and serum AAG levels in Whites, but unexpectedly not in Blacks. This novel observation suggests that genetic determinants of AAG levels in Blacks are unrelated to the UGT2B17 CNV. This study replicates the results that show an association of UGT215 D85Y with an increased prostate cancer risk.

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“…DHT may have been sulfonated 29 for paracrine reuse or metabolized to androstanediol or AND in BP or CaP tissue. AND and androstanediol can be glucuronidated and trafficked from tissue, 30 but glucuronidated metabolites may have been expelled more efficiently by BP than CaP cells. Oesterling et al 31 reported that adrenal androgens produced by the adrenal gland were not sufficient for prostate growth and development in men diagnosed with hypogonadotropic hypogonadism.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Prostate Cancer in a Functional Eunuch

Stocking

Fiandalo

Pop

et al. 2016

J Natl Compr Canc Netw

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Background Eunuchs rarely, if ever, develop prostate cancer (CaP). This article reports on a 62-year-old functional eunuch from prepubertal mumps orchitis who developed clinically localized CaP. Methods Serum and CaP and benign prostate tissue androgen levels were measured using a validated liquid chromatography-tandem mass spectrometry assay. The assay measures testosterone; dihydrotestosterone (DHT); the adrenal androgens, androstenedione and dehydroepiandrosterone; and the androgen metabolites, androsterone and androstanedione. Gene and protein expression levels of androgen metabolism enzymes, and androgen receptor and androgen-regulated genes were measured using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry, respectively. Results Intracrine androgen metabolism produced tissue DHT when serum and tissue testosterone levels were castrate and undetectable, respectively. Androgen receptor, androgen-regulated, and androgen metabolism enzyme genes were expressed but at lower levels in CaP than benign tissues. Conclusions DHT was synthesized using the primary backdoor androgen metabolism pathway and not using androstenedione or dehydroepiandrosterone via the frontdoor or secondary backdoor pathways.

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Correlation between circulatory, local prostatic, and intra‐prostatic androgen levels

Abstract: These results indicate that local prostatic DHT production has an influence on systemic serum DHT levels. Moreover, our results support the evidence that the prostate is the main DHT producer and that UGTs are important in the intra-prostatic regulation of androgens.

Cited by 28 publications

References 18 publications

Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

Association of Uridine Diphosphate-Glucuronosyltransferase 2B Gene Variants with Serum Glucuronide Levels and Prostate Cancer Risk

Characterization of Prostate Cancer in a Functional Eunuch

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