title: Induction of UDP-glucuronosyltransferase 2B15 gene expression by the major active metabolites of tamoxifen, 4-hydroxytamoxifen and endoxifen, in breast cancer cells.
abstract: We previously reported upregulation of UGT2B15 by 17β-estradiol in breast cancer MCF7 cells via binding of the estrogen receptor α (ERα) to an estrogen response unit (ERU) in the proximal UGT2B15 promoter. In the present study, we show that this ERα-mediated upregulation was significantly reduced by two ER antagonists (fulvestrant and raloxifene) but was not affected by a third ER antagonist, 4-hydroxytamoxifen (4-OHTAM), a major active tamoxifen (TAM) metabolite. Furthermore, we found that, similar to 17β-estradiol, 4-OHTAM and endoxifen (another major active TAM metabolite) elevated UGT2B15 mRNA levels, and that this stimulation was significantly abrogated by fulvestrant. Further experiments using 4-OHTAM revealed a critical role for ERα in this regulation. Specifically; knockdown of ERα expression by anti-ERα small interfering RNA reduced the 4-OHTAM-mediated induction of UGT2B15 expression; 4-OHTAM activated the wild-type but not the ERU-mutated UGT2B15 promoter; and chromatin immunoprecipitation assays showed increased ERα occupancy at the UGT2B15 ERU in MCF7 cells upon exposure to 4-OHTAM. Together, these data indicate that both 17β-estradiol and the antiestrogen 4-OHTAM upregulate UGT2B15 in MCF7 cells via the same ERα-signaling pathway. This is consistent with previous observations that both 17β-estradiol and TAM upregulate a common set of genes in MCF7 cells via the ER-signaling pathway. As 4-OHTAM is a UGT2B15 substrate, the upregulation of UGT2B15 by 4-OHTAM in target breast cancer cells is likely to enhance local metabolism and inactivation of 4-OHTAM within the tumor. This represents a potential mechanism that may reduce TAM therapeutic efficacy or even contribute to the development of acquired TAM resistance.
authors: 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: Apichaya
authors: A
authors: Chanawong
authors: 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: Dong Gui
authors: DG
authors: Hu
authors: 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: Robyn
authors: R
authors: Meech
authors: 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: Peter I
authors: PI
authors: Mackenzie
authors: Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia ross.mckinnon@flinders.edu.au.
authors: Ross A
authors: RA
authors: McKinnon
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015507:Drugs, Investigational / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects*; D065171:Estrogen Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015507:Drugs, Investigational; C506487:ESR1 protein, human; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D013629:Tamoxifen; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human