1. Induction of UDP-glucuronosyltransferase 2B15 gene expression by the major active metabolites of tamoxifen, 4-hydroxytamoxifen and endoxifen, in breast cancer cells.
- Author
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Chanawong A, Hu DG, Meech R, Mackenzie PI, and McKinnon RA
- Subjects
- Antineoplastic Agents, Hormonal antagonists & inhibitors, Antineoplastic Agents, Hormonal metabolism, Breast Neoplasms metabolism, Drugs, Investigational chemistry, Drugs, Investigational metabolism, Estrogen Receptor Antagonists chemistry, Estrogen Receptor Antagonists metabolism, Estrogen Receptor alpha agonists, Estrogen Receptor alpha antagonists & inhibitors, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Female, Genes, Reporter drug effects, Glucuronosyltransferase antagonists & inhibitors, Glucuronosyltransferase genetics, Humans, MCF-7 Cells, Mutation, Neoplasm Proteins agonists, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Promoter Regions, Genetic drug effects, RNA Interference, Response Elements drug effects, Signal Transduction drug effects, Substrate Specificity, Tamoxifen antagonists & inhibitors, Tamoxifen metabolism, Tamoxifen pharmacology, Antineoplastic Agents, Hormonal pharmacology, Breast Neoplasms drug therapy, Drugs, Investigational pharmacology, Enzyme Induction drug effects, Estrogen Receptor Antagonists pharmacology, Glucuronosyltransferase metabolism, Tamoxifen analogs & derivatives
- 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., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.) more...
- Published
- 2015
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