title: MiR-487a resensitizes mitoxantrone (MX)-resistant breast cancer cells (MCF-7/MX) to MX by targeting breast cancer resistance protein (BCRP/ABCG2).
abstract: Breast cancer resistance protein (BCRP/ABCG2) specifically transports various chemotherapeutic agents and is involved in the development of multidrug resistance (MDR) in cancer cells. MicroRNAs (miRNAs) can play an important role in modulating the sensitivity of cancer cells to chemotherapeutic agents. Therefore, after confirming that BCRP was increased in the mitoxantrone (MX)-resistant MCF-7 breast cancer cell line MCF-7/MX compared with its parental sensitive MCF-7 cell line, we aimed to explore the miRNAs that regulate BCRP expression and sensitize breast cancer cells to chemotherapeutic agents. In the present study, bioinformatic analysis indicated that miR-487a was one of the miRNAs that could bind to the 3' untranslated region (3'UTR) of BCRP. Quantitative RT-PCR (qRT-PCR) analysis demonstrated that the expression of miR-487a was reduced in MCF-7/MX cells, and a luciferase reporter assay demonstrated that miR-487a directly bound to the 3'UTR of BCRP. Moreover, ectopic miR-487a down-regulated BCRP expression at the mRNA and protein levels, increasing the intracellular accumulation and cytotoxicity of MX in resistant MCF-7/MX breast cancer cells. Meanwhile, inhibition of miR-487a increased BCRP expression at the mRNA and protein levels and induced MX resistance in sensitive MCF-7 breast cancer cells. Furthermore, the reduced expression of BCRP and increased antitumor effects of MX were also detected in MCF-7/MX xenograft tumors treated with the miR-487a agmir. Thus, our results suggested that miR-487a can directly regulate BCRP expression and reverse chemotherapeutic drug resistance in a subset of breast cancers.
authors.affiliation: Department of Pharmacology, China Medical University, North 2nd Road 92, Heping District, Shenyang 110001, Liaoning Providence, PR China.
authors.forename: Meng-Tao
authors.initials: MT
authors.lastname: Ma
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Xu-Yang
authors.initials: XY
authors.lastname: Jiao
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Bai
authors.forename: Zhao-Jin
authors.initials: ZJ
authors.lastname: Yu
authors.forename: Hui-Zhe
authors.initials: HZ
authors.lastname: Wu
authors.forename: Ming-Li
authors.initials: ML
authors.lastname: Sun
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Song
authors.forename: Min-Jie
authors.initials: MJ
authors.lastname: Wei
mesh_terms: D020413:3' Untranslated Regions; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008942:Mitoxantrone / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000235:genetics*; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: D020413:3' Untranslated Regions; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C568526:MIRN487 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D008942:Mitoxantrone
keywords: BCRP; Breast cancer; MiR-487a; Multidrug resistance