PT - JOURNAL ARTICLE AU - Apichaya Chanawong AU - Dong Gui Hu AU - Robyn Meech AU - Peter I. Mackenzie AU - Ross A. McKinnon TI - Induction of UDP-Glucuronosyltransferase 2B15 Gene Expression by the Major Active Metabolites of Tamoxifen, 4-Hydroxytamoxifen and Endoxifen, in Breast Cancer Cells AID - 10.1124/dmd.114.062935 DP - 2015 Jun 01 TA - Drug Metabolism and Disposition PG - 889--897 VI - 43 IP - 6 4099 - http://dmd.aspetjournals.org/content/43/6/889.short 4100 - http://dmd.aspetjournals.org/content/43/6/889.full SO - Drug Metab Dispos2015 Jun 01; 43 AB - 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.