Androgen and estrogen receptors in breast cancer co-regulate human UDP-glucuronosyltransferases 2B15 and 2B17

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 (ERα), 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, ERα, 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 5α dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half site 30 to the FOXA1 and ERα 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 ERα₊ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα 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 ERα₊ breast cancer, which may have subtypespecific consequences for disease progression and outcomes.