Hormonal regulation of BCRP expression in human placental BeWo cells

Purpose. We investigated whether the pregnancy-related hormones, estriol (E(3)), testosterone, human placental lactogen (hPL), human prolactin (hPRL), and human chorionic gonadotropin (hCG) affect BCRP expression in human placental BeWo cells. Materials and methods. The effects of these hormones on BCRP protein and mRNA expression in BeWo cells were determined by immunoblotting and quantitative real-time RT-PCR, respectively. The effects of these hormones on membrane localization of BCRP in BeWo cells were examined by immunofluorescent confocal microscopy. Results. E(3), hPL, and hPRL significantly increased BCRP protein and mRNA approximately two to threefold at physiological concentrations. Induction of BCRP by E(3) was abrogated by the estrogen receptor (ER) antagonist ICI-182,780. However, knock-down of ER alpha by RNA interference did not abolish the inductive effect of E(3). Testosterone by itself did not affect BCRP expression at physiological concentrations. However, testosterone together with 17 beta-estradiol (E(2)) increased BCRP protein and mRNA approximately twofold, and this induction was abolished by ICI-182,780 or the testosterone receptor (TR) antagonist flutamide or knock-down of ER alpha expression. Further analysis revealed that E(2) increased TR mRNA approximately 5.9-fold, suggesting that testosterone in combination with E(2) increases BCRP expression, possibly through E(2)-mediated up-regulation of TR. hCG at physiological concentrations had no effect on BCRP expression. Conclusions. E(3), hPL, hPRL, and testosterone in combination with E(2) may up-regulate BCRP expression in the placenta during pregnancy.