Transcriptional upregulation of breast cancer resistance protein by 17beta-estradiol in ERalpha-positive MCF-7 breast cancer cells.
OBJECTIVE
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 17beta-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 (ERalpha)-positive MCF-7 and ERalpha-negative MDA-MB-231 breast cancer cell lines.


RESULTS
17beta-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 ERalpha are essential for transcriptional activation of BCRP by 17beta-estradiol.


CONCLUSIONS
Taken together, our findings indicate that BCRP expression is upregulated by 17beta-estradiol via a novel pretranscriptional mechanism which might be involved in 17beta-estradiol-ER complexes binding to the ERE of BCRP promoter via the classical pathway to activate transcription of the BCRP gene.
Zhang
Yuhua
Y
Department of Pathology, Qilu Hospital School of Medicine, Jinan, People's Republic of China.
Zhou
Gengyin
G
Wang
Huaiping
H
Zhang
Xiaofang
X
Wei
Fulan
F
Cai
Yongping
Y
Yin
Deling
D
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018014:Gene Transfer Techniques; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D004958:Estradiol