Regulation of BCRP/ABCG2 Expression By Progesterone And 17β-Estradiol in Human Placental BeWo Cells

The breast cancer resistance protein (BCRP) is abundant in the placenta and protects the fetus by limiting placental drug penetration. We hypothesize that pregnancyspecific hormones regulate BCRP expression. Hence, we examined the effects of progesterone (P4) and 17β-estradiol (E2) on BCRP expression in the human placental BeWo cells. P4 and E2 significantly increased and decreased BCRP protein and mRNA, respectively. Likewise, treatment with P4 and E2 respectively increased and decreased fumitremorgin C-inhibitable mitoxantrone efflux activity of BeWo cells. Reduction in BCRP expression by E2 was abrogated by the estrogen receptor (ER) antagonist ICI 182,780. However, the progesterone receptor (PR) antagonist RU 486 had no effect on P4-mediated induction of BCRP. P4 together with E2 further increased BCRP protein and mRNA, compared with P4 treatment alone. This combined effect on BCRP expression was abolished by RU 486 or ICI 182,780 or both. Further analysis revealed that E2 significantly decreased ERβ mRNA, and strongly induced PRB mRNA in a dosedependent manner, but had no effect on PRA and ERα. P4 alone had no significant effect on mRNA of ERα, ERβ, PRA and PRB. E2 in combination with P4 increased PRB mRNA, but the level of induction was significantly reduced compared with E2 treatment alone. Taken together, these results indicate that E2 by itself likely down-regulates BCRP expression through an ER, possibly ERβ. P4 alone up-regulates BCRP expression via a mechanism other than PR. P4 in combination with E2 further increases BCRP expression, presumably via a non-classical PR and/or E2-mediated synthesis of PRB.