Oncotarget

Research Papers:

miR-145 sensitizes breast cancer to doxorubicin by targeting multidrug resistance-associated protein-1

Man Gao, Lingling Miao, Mingxia Liu, Chenggang Li, Cunzhi Yu, Hong Yan, Yongxiang Yin, Yizheng Wang, Xinming Qi _ and Jin Ren

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Oncotarget. 2016; 7:59714-59726. https://doi.org/10.18632/oncotarget.10845

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Abstract

Man Gao1, Lingling Miao1, Mingxia Liu1, Chenggang Li1, Cunzhi Yu1, Hong Yan1, Yongxiang Yin2, Yizheng Wang3, Xinming Qi1, Jin Ren1

1Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, CAS., Shanghai, P.R. China

2Department of Pathology, Wuxi Maternity and Children Health Hospital Affiliated Nanjing Medical University, Wuxi, China

3The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China

Correspondence to:

Xinming Qi, email: xmqi@cdser.simm.ac.cn

Jin Ren, email: jren@cdser.simm.ac.cn

Keywords: breast cancer, MRP1, miRNA, chemoresistance, doxorubicin

Received: August 11, 2015     Accepted: June 09, 2016     Published: July 26, 2016

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.


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