Journal
ONCOLOGY
Volume 71, Issue 5-6, Pages 446-455Publisher
KARGER
DOI: 10.1159/000108594
Keywords
BCRP; breast cancer; 17 beta-estradiol; gene regulation; promoter
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Objectives: Breast cancer resistance protein ( BCRP) confers resistance to certain anticancer drugs such as mitoxantrone, topotecan and SN- 38. A putative estrogen response element ( ERE) was located in the promoter region of the BCRP gene. The present study aimed to investigate whether human BCRP expression is regulated pretranscriptionally by 17 beta-estradiol. Methods: Two recombinant plasmids ( pcDNA3-promoter- BCRP and pcDNA3- CMV- BCRP) were designed to express the full- length BCRP cDNA enforced driven by its endogenous promoter containing a functional ERE and a control constitutive cytomegalovirus ( CMV) promoter, respectively, which were transfected into estrogen receptor alpha (ER alpha)-positive MCF-7 and ER alpha-negative MDA-MB-231 breast cancer cell lines. Results: 17 beta-Estradiol significantly upregulated BCRP mRNA and protein expression in a dose- dependent manner, and the effect was abolished by the antiestrogen tamoxifen. Furthermore, electrophoretic mobility shift assays demonstrated that the putative ERE in the promoter region of the BCRP gene and ER alpha are essential for transcriptional activation of BCRP by 17 beta-estradiol. Conclusions: Taken together, our findings indicate that BCRP expression is upregulated by 17 beta-estradiol via a novel pretranscriptional mechanism which might be involved in 17 beta-estradiol-ER complexes binding to the ERE of BCRP promoter via the classical pathway to activate transcription of the BCRP gene. Copyright (C) 2006 S. Karger AG, Basel.
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