Exemestane (EXE) is an aromatase inhibitor indicated for endocrine therapy of breast cancer in post-menopausal women. The primary active metabolite of EXE, 17-hydroexemestane (17-HE), is inactivated via glucuronidation, mainly by UGT2B17. UGT2B17 also has a primary role in inactivation of endogenous androgens testosterone and dihydrotestosterone (DHT) and may play an important role in regulation of breast and prostate tumour intracrinology. We recently reported that UGT2B17 could be induced by both estrogenic and androgenic ligands in breast cancer cells via binding of the estrogen receptor alpha (ERα) or the androgen receptor (AR) to a complex regulatory unit in the proximal UGT2B17 promoter. In this study we show that both EXE and 17-HE increase UGT2B17 mRNA levels in breast cancer MCF-7 and MDA-MB-453 cells, and increase glucuronidation of UGT2B17 substrates, including 17-HE and androsterone. Using antagonists of ERα and AR, as well as siRNA-mediated inhibition, we demonstrate that EXE and 17-HE induce UGT2B17 expression primarily via the AR. This result is consistent with previous reports that 17-HE can act as an AR ligand. In vitro studies suggest that multiple steroid-responsive DNA elements within the proximal promoter are involved in the response to 17-HE-liganded AR. The upregulation of UGT2B17 by EXE and 17-HE in breast cancer cells might enhance the local metabolism of 17-HE as well as that of endogenous androgens, hence impacting on treatment outcomes.
- The American Society for Pharmacology and Experimental Therapeutics