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First published on November 27, 2007; DOI: 10.1124/mol.107.041087

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Received for publication August 21, 2007.
Revised November 21, 2007.
Accepted for publication November 26, 2007.

Progesterone Receptor Isoforms, PRA and PRB, Differentially Regulate Expression of the Breast Cancer Resistance Protein (BCRP) in Human Placental Choriocarcinoma BeWo Cells

Honggang Wang 1, Eun-Woo Lee 1, Lin Zhou 1, Peter C. K. Leung 2, Douglas Ross 3, Jashvant D. Unadkat 1, Qingcheng Mao 1*

1 University of Washington 2 The University of British Columbia 3 University of Maryland

* Address correspondence to: E-mail: qmao{at}u.washington.edu

Abstract

BCRP plays a significant role in drug disposition and in conferring multidrug resistance in cancer cells. Previous studies have shown that steroid hormones such as 17{beta}-estradiol and progesterone can affect BCRP expression in cancer cells. In this study, we investigated the molecular mechanism by which BCRP expression in human placental choriocarcinoma BeWo cells is regulated by progesterone. Transfection of the progesterone receptor (PR) isoforms, PRA and PRB, resulted in a similarly increased expression of PRA and PRB, respectively. However, progesterone significantly increased BCRP expression and activity only in PRB-transfected cells. This stimulatory effect of progesterone was abrogated by the PR antagonist RU-486. Consistently, transcriptional activity of the BCRP promoter was induced 2-6-fold by 10-8-10-5 M progesterone in PRB-transfected cells. Progesterone had little effect on BCRP expression and activity, and transcriptional activity of the BCRP promoter in PRA-transfected cells; however, co-transfection of PRA and PRB significantly decreased the progesterone-response compared with that in cells transfected with only PRB. Mutations in a novel progesterone response element (PRE) identified between -243 to -115 bp of the BCRP promoter region significantly attenuated the progesterone-response in PRB-transfected cells, and deletion of the PRE nearly completely abrogated the progesterone effect. Specific binding of both PRA and PRB to the BCRP promoter through the identified PRE was confirmed using the electrophoretic mobility shift assay. Collectively, progesterone induces BCRP expression in BeWo cells via PRB, but not PRA. PRA represses the PRB activity. Thus, PRA and PRB differentially regulate BCRP expression in BeWo cells.


Key words: Sex hormones, Regulation of gene expression, Regulation - transcriptional


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M. Vore and M. Leggas
Progesterone Acts via Progesterone Receptors A and B to Regulate Breast Cancer Resistance Protein Expression
Mol. Pharmacol., March 1, 2008; 73(3): 613 - 615.
[Abstract] [Full Text] [PDF]


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