Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Abstract

Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERa), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDPglucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced diseasespecific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERa. In cell line models, ERa, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERa activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5a-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3 0 to the FOXA1 and ERa-binding sites. Although AR and FOXA1 bound the UGT promoters in ARpositive/ERa-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERa þ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERa binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERa þ breast cancer, which may have subtypespecific consequences for disease progression and outcomes.

Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma

“…No studies in PCa were available on the interaction between LDHA and ESR1. Interestingly, among the common up-regulated targets, UGT2B15 and HOTAIR were described to be inhibited by AR in prostate tumors [17,34] and activated by ESR1 [20,35]. AR specific targets were mainly involved in sulfur compound biosynthetic process, response to lipid, response to steroid hormone, regulation of ion homeostasis, signal transduction, epithelial cell development.…”

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...…”

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex

“…UGT2B17 also appears to play a critical role in the metabolism of tobaccospecific carcinogens and the risk of lung cancer (Lazarus et al, 2005;Chen et al, 2016a). In addition, high intratumoral UGT2B17 expression levels correlate with better survival outcomes in patients with breast cancer (Hu et al, 2016). Besides its role in disease pathophysiology, the UGT2B17 gene deletion is associated with false-negative doping test results, which in turn is linked to variable testosterone metabolism (Schulze et al, 2008).…”