Regulation of BCRP/ABCG2 expression by progesterone and 17beta-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 pregnancy-specific hormones regulate BCRP expression. Hence, we examined the effects of progesterone (P4) and 17beta-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 beta mRNA and strongly induced PR(B) mRNA in a dose-dependent manner but had no effect on PR(A) and ER alpha. P4 alone had no significant effect on mRNA of ER alpha, ER beta, 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 beta. 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).
Wang
Honggang
H
Dept. of Pharmaceutics, School of Pharmacy, Univ. of Washington, Seattle, WA 98195-7610, USA.
Zhou
Lin
L
Gupta
Anshul
A
Vethanayagam
R Robert
RR
Zhang
Yi
Y
Unadkat
Jashvant D
JD
Mao
Qingcheng
Q
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D008942:Mitoxantrone / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000235:genetics
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009363:Neoplasm Proteins; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D000077267:Fulvestrant; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D008942:Mitoxantrone