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

• Published in: American journal of physiology: endocrinology and metabolism 2006-05, Vol.290 (5), p.E798-E807
• Main Authors: Wang, Honggang, Zhou, Lin, Gupta, Anshul, Vethanayagam, R. Robert, Zhang, Yi, Unadkat, Jashvant D., Mao, Qingcheng
• Format: Article
• Language: English
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00397.2005

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 (P 4 ) and 17β-estradiol (E 2 ) on BCRP expression in the human placental BeWo cells. P 4 and E 2 significantly increased and decreased BCRP protein and mRNA, respectively. Likewise, treatment with P 4 and E 2 increased and decreased, respectively, fumitremorgin C-inhibitable mitoxantrone efflux activity of BeWo cells. Reduction in BCRP expression by E 2 was abrogated by the estrogen receptor (ER) antagonist ICI-182,780. However, the progesterone receptor (PR) antagonist RU-486 had no effect on P 4 -mediated induction of BCRP. P 4 together with E 2 further increased BCRP protein and mRNA compared with P 4 treatment alone. This combined effect on BCRP expression was abolished by RU-486, ICI-182,780, or both. Further analysis revealed that E 2 significantly decreased ERβ mRNA and strongly induced PR B mRNA in a dose-dependent manner but had no effect on PR A and ERα. P 4 alone had no significant effect on mRNA of ERα, ERβ, PR A , and PR B . E 2 in combination with P 4 increased PR B mRNA, but the level of induction was significantly reduced compared with E 2 treatment alone. Taken together, these results indicate that E 2 by itself likely downregulates BCRP expression through an ER, possibly ERβ. P 4 alone upregulates BCRP expression via a mechanism other than PR. P 4 in combination with E 2 further increases BCRP expression, presumably via a nonclassical PR- and/or E 2 -mediated synthesis of PR B .