Novel identification of UDP-glucuronosyltransferase 1A10 as an estrogen-regulated target gene

Recently, we have shown that UGT1A10 is actively involved in the inactivation of E-1, E-2, and their 2- and 4-hydroxylated derivatives. In the present study, we show for the first time that treatment of the MCF-7 ER-positive breast cancer cell line with E-2 produces a dose-dependent up-regulation of UGT1A10 mRNA levels, followed by a steady down-regulation. In contrast, E-2 did not stimulate mRNA expression in the MDA-MB-231 (ER)-negative breast cancer cell line. Expression of UGT1A10 mRNA was blocked by the antiestrogen, ICI 182,780, but not by the transcriptional inhibitor, actinomycin-D. These findings suggest that regulation of UGT1A10 mRNA might be a primary transcriptional response mediated through the ER. Expression of UGT1A10 mRNA was also stimulated by other estrogenic compounds including propylpyrazoletriol (PPT) and genistein (Gen). Exposure of MCF-7 cells to 0.1 nM E-2 up-regulated, and then down-regulated, UGT1A protein and enzymatic activity toward E-2 at 10 nM E-2 as determined by Western blot and glucuronidation activity assays. Collectively, these results suggest that induction of UGT1A10 mRNA expression by E-2 might be mediated through ER, and that this isoform is a novel, estrogen-regulated target gene in MCF-7, ER-positive human breast cancer cells. The finding of E-2-induced expression of UGT1A10 mRNA, followed by the down-regulation of UGT1A10 at pharmacological concentrations of E2, might have a significant moderating effect on E-2 availability for ER and estrogen clearance, thereby promoting the signaling of E-2 in breast cancer cells. (C) 2007 Elsevier Inc. All rights reserved.