title: Exemestane and Its Active Metabolite 17-Hydroexemestane Induce UDP-Glucuronosyltransferase (UGT) 2B17 Expression in Breast Cancer Cells.
abstract: Exemestane (EXE) is an aromatase inhibitor indicated for endocrine therapy of breast cancer in postmenopausal women. The primary active metabolite of EXE, 17-hydroexemestane (17-HE), is inactivated via glucuronidation, mainly by UDP-glucuronosyltransferase 2B17 (UGT2B17). UGT2B17 also has a primary role in inactivation of endogenous androgens testosterone and dihydrotestosterone and may play an important role in regulation of breast and prostate tumor intracrinology. We recently reported thatUGT2B17could be induced by both estrogenic and androgenic ligands in breast cancer cells via binding of the estrogen receptorα(ERα) or the androgen receptor (AR) to a complex regulatory unit in the proximalUGT2B17promoter. 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 ERαand AR as well as inhibition mediated by small interfering RNA (siRNA) we demonstrate that EXE and 17-HE induceUGT2B17expression 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 up-regulation ofUGT2B17by 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 potentially on treatment outcomes.
authors.affiliation: Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia.
authors.forename: Apichaya
authors.initials: A
authors.lastname: Chanawong
authors.affiliation: Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Mackenzie
authors.affiliation: Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: McKinnon
authors.affiliation: Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia.
authors.forename: Dong Gui
authors.initials: DG
authors.lastname: Hu
authors.affiliation: Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia robyn.meech@flinders.edu.au.
authors.forename: Robyn
authors.initials: R
authors.lastname: Meech
mesh_terms: D000730:Androstadienes / Q000378:metabolism* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D015778:Minor Histocompatibility Antigens; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human; C056516:exemestane