title: miR-145 sensitizes breast cancer to doxorubicin by targeting multidrug resistance-associated protein-1.
abstract: Multidrug resistance-associated protein 1 (MRP1) is an important efflux transporter and overexpression of MRP1 usually leads to chemoresistance in breast cancer. Here, we found MRP1 overexpressed in human breast cancer tissues and breast cancer cell lines (compared with normal breast tissues and cell line, respectively). And MRP1 level increased in doxorubicin resistant MCF-7 cells compared with parental MCF-7 cells. Increasing evidences suggest microRNAs (miRNAs) influence chemotherapy response. We found miR-145 level decreased in human breast cancer tissues, breast cancer cell lines and doxorubicin resistant MCF-7 cells, and inversely correlated with MRP1 expression level. In the process of constructing MCF-7 doxorubicin resistant cell line, escalating doxorubicin markedly decreased miR-145 level, following by increased MRP1 level. Further study showed, miR-145 suppressed MRP1 expression by directly targeting MRP1 3'-untranslated regions. Overexpression of miR-145 sensitized breast cancer cells to doxorubicin in vitro and enhanced to doxorubicin chemotherapy in vivo through inducing intracellular doxorubicin accumulation via inhibiting MRP1. Taken together, our study revealed miR-145 sensitizes breast cancer to doxorubicin by targeting MRP1 and indicated the potential application in developing MRP1 inhibitor.
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Man
authors.initials: M
authors.lastname: Gao
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Miao
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Liu
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Cunzhi
authors.initials: C
authors.lastname: Yu
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Pathology, Wuxi Maternity and Children Health Hospital Affiliated Nanjing Medical University, Wuxi, China.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Xinming
authors.initials: X
authors.lastname: Qi
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020413:3' Untranslated Regions; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C541010:MIRN145 microRNA, human; C421109:multidrug resistance-associated protein 1
keywords: MRP1; breast cancer; chemoresistance; doxorubicin; miRNA