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). Herein, the expression and regulation of two androgen inactivating UDP-glucuronosyltransferase (UGT) enzymes, UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups of breast cancer. Expression of these genes was highest in ERα+ cases, and in cell line models, ERα, FOXA1 and AR co-operatively increased transcription via tandem binding events at their proximal promoters. ERα 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 3 to the FOXA1 and ERα binding sites. Although AR and FOXA1 bound the UGT promoters in AR+, ERα-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 up-regulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at their promoters in a small cohort of primary tumors and distant metastases. Collectively, this data provides insight into sex steroid receptor-mediated regulation of androgen inactivating enzymes in ERα+ breast cancer, which may have subtype-specific consequences for disease progression and outcomes.
Presenting Author: Theresa Hickey, Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, DX Number 650 801, The University of Adelaide SA 5005, Australia. Email: firstname.lastname@example.org