Different Modulation of ER‐Mediated Transactivation by Xenobiotic Nuclear Receptors Depending on the Estrogen Response Elements and Estrogen Target Cell Types

Abstract

Recent studies demonstrated that constitutive androstane receptor (CAR) inhibits ER-mediated transactivation of both endogenous and synthetic estrogen responsive promotor in Hep G2. Whereas steroid and xenobiotic receptor (SXR) but not peroxisome proliferator-activated receptor-gamma (PPAR-gamma) was also reported to repress estrogen receptor (ER) transactivation of the synthetic 4ERE in Hep G2, the effects of these xenobiotic nuclear receptors (XNRs) on the endogenous estrogen responsive promotor remain to be determined. Effects of CAR, SXR, and PPAR-gamma on ER transactivation were also examined in three different kinds of breast cancer cell lines. However, except in MCF-7, studies were limited either in single dose response (MDA-MB-231) or with CAR only (MCF-7-K3). And there is presently no report on the effects of CAR, SXR, and PPAR-gamma on ER-mediated transactivation in ovarian-derived CHO-S cells. Accordingly, this article further examined the effects of the endogenous vitellogenin B1 estrogen responsive promotor on the SXR- and PPAR-gamma-modulated ER transactivation in Hep G2, and either dose-dependent or single dose effects of SXR, PPAR-gamma, and CAR in two different breast cancer cell lines and the ovarian-derived cell line respectively, on the ER-mediated transactivation of the synthetic (4ERE)-tk-luciferase reporter. Consistent with the previous report, CAR significantly repressed ER-mediated transactivation of the endogenous vitellogenin B1 promotor in Hep G2 cells. However, contrary to the effects on the synthetic promotor, PPAR-gamma potentiated whereas SXR did not have any effects on the ER transactivation of the vitellogenin promotor in Hep G2. In the breast cancer cell line of MDA-MB-231 in which endogenous ER is known not to be expressed, CAR modestly stimulated ER transactivation of the synthetic 4ERE in a low dose whereas both SXR and PPAR-gamma did not have any effects in all doses examined (20-500 ng). And in both CHO-S and estrogen-independent breast cancer cell line, MCF-7-K3, none of the three xenobiotic receptors significantly influenced the ER-mediated 4ERE transactivation in all doses examined. XNRs modulate ER-mediated transactivation depending on the estrogen response elements (EREs) and estrogen target cell types.