Breast cancer resistance protein (BCRP/ ABCG2), an ATP-binding cassette half transporter, confers multidrug resistance (MDR) to a series of antitumor agents such as mitoxantrone, daunorubicin, SN-38, and topotecan, and often limits the efficacy of chemotherapy. Recent studies have indicated that a putative estrogen response element (ERE) is located in the promoter region of the BCRP gene. However, whether and how BCRP is regulated transcriptionally by toremifene (TOR) remains unknown. In the present study, two plasmid vectors have been designed to express the wild-Type full-length BCRP cDNA enforced driven by its endogenous promoter containing a functional ERE and a constitutive cytomegalovirus (CMV) promoter as control, respectively, which were transfected into estrogenresponsive MCF-7 and estrogen-independent MDA-MB-231 human breast adenocarcinoma cell lines. We showed that toremifene alone significantly downregulated BCRP mRNA and protein levels in estrogen receptor a (ERa)-positiveMCF- 7 cells in a dose-dependent manner, and the inhibitory effect was partially reversed by estrone (E1). Furthermore, gel shift assays demonstrated that specific binding of ERa to the ERE in the BCRP promoter is essential for transcriptional inhibition of BCRP by toremifene. Interestingly, toremifene alone increased the cellular accumulation of mitoxantrone inBCRPtransfected cells, suggesting that TOR indeed inhibits BCRPmediated drug efflux and overcome drug resistance. To the best of our knowledge, this is the first report describing a direct effect of toremifene on BCRP. Our results thus indicate that toremifene by itself downregulates BCRP expression to reverse BCRP-mediated atypical multidrug resistance via a novel transcriptionally mechanism, which might be involved inTOR-ERcomplexes binding to theEREofBCRP promoter to repress transcription of BCRP gene.
Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etsu-works-18044 |
Date | 01 October 2010 |
Creators | Zhang, Yuhua, Wang, Huaiping, Wei, Lijing, Li, Guang, Yu, Jin, Gao, Yan, Gao, Peng, Zhang, Xiaofang, Wei, Fulan, Yin, Deling, Zhou, Gengyin |
Publisher | Digital Commons @ East Tennessee State University |
Source Sets | East Tennessee State University |
Detected Language | English |
Type | text |
Source | ETSU Faculty Works |
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