Abstract 3448: Overexpression of the steroid inactivating UGT2B28 enzyme is associated with high circulating androgens, tumor aggressiveness and adverse prostate cancer outcome

Abstract

Abstract Androgen inactivation occurs mainly through the glucuronidation conjugative reaction mediated by uridine diphospho-glucuronosyltransferase enzymes, namely UGT2B28. This metabolic pathway controls systemic and local androgen bioavailability along with other biotransformation and transport pathways. In this study, we examined the relationship between UGT2B28 protein expression, circulating steroid levels and prostate cancer phenotype. To study distribution of the UGT2B28 protein in prostatic tissues, we used a specific antipeptide antibody displaying no cross-reactivity against highly identical UGT2B family members. Findings revealed that UGT2B28 cytoplasmic staining of secretory cells was distinctive of early stage tumorigenesis (i.e. prostatic intraepithelial neoplasia) and cancer cells with a variable nuclear staining, whereas normal prostate presented only nuclear enzyme expression. Using tissue microarray analysis, we analyzed 239 localized prostate cancer cases that underwent radical prostatectomy. Compared to patients with prostate tumors displaying absent or weak UGT2B28 staining, those with tumors presenting strong UGT2B28 nuclear expression had significantly lower PSA levels at diagnosis (20%; p = 0.043). UGT2B28 expression in the cytoplasm was also correlated with Gleason scores (p≤0.03) and nodal invasion status (p = 0.024). After adjustments for known prognostic markers including PSA, Gleason score, margin and nodal status, tumor size, smoking and germline UGT2B28 deletion status, overexpression of the UGT2B28 protein was an adverse and independent prognostic factor associated with disease recurrence and/or death (HR = 2.82; 95%CI, 1.09-7.36; p = 0.033). Remarkably, prostatic overexpression of UGT2B28 concurs with 30% higher circulating levels of testosterone (p = 0.004) and dihydrotestosterone (p = 0.002), measured by mass spectrometry. Our observations demonstrate that an increased expression of the UGT2B28 enzyme is associated with circulating steroid hormone levels, disease aggressiveness and risk of cancer progression. Citation Format: Anaïs Belledant, Hélène Hovington, Hervé Brisson, Bernard Têtu, Yves Fradet, Louis Lacombe, Patrick Caron, Chantal Guillemette, Eric Lévesque. Overexpression of the steroid inactivating UGT2B28 enzyme is associated with high circulating androgens, tumor aggressiveness and adverse prostate cancer outcome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3448. doi:10.1158/1538-7445.AM2015-3448