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Regulation of BCRP/ABCG2 expression by progesterone and 17-estradiol in human placental BeWo cells

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington

Submitted 29 August 2005 ; accepted in final form 7 December 2005

The breast cancer resistance protein (BCRP) is abundant in the placenta and protects the fetus by limiting placental drug penetration. We hypothesize that pregnancy-specific hormones regulate BCRP expression. Hence, we examined the effects of progesterone (P₄) and 17-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 increased and decreased, respectively, 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, ICI-182,780, or both. Further analysis revealed that E₂ significantly decreased ER mRNA and strongly induced PR_B mRNA in a dose-dependent manner but had no effect on PR_A and ER. P₄ alone had no significant effect on mRNA of ER, ER, PR_A, and PR_B. E₂ in combination with P₄ increased PR_B mRNA, but the level of induction was significantly reduced compared with E₂ treatment alone. Taken together, these results indicate that E₂ by itself likely downregulates BCRP expression through an ER, possibly ER. P₄ alone upregulates BCRP expression via a mechanism other than PR. P₄ in combination with E₂ further increases BCRP expression, presumably via a nonclassical PR- and/or E₂-mediated synthesis of PR_B.

hormonal regulation; ATP-binding cassette transporter; pregnancy

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