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

摘要

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 0.1nM E(2) up-regulated, and then down-regulated, UGT1A protein and enzymatic activity toward E(2) at 10nM 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 E(2), 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.