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MiR-181a enhances drug sensitivity in mitoxantone-resistant breast cancer cells by targeting breast cancer resistance protein (BCRP/ABCG2)

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Abstract

Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) mediates multidrug resistance (MDR) in breast cancers. In this study, we aimed to investigate the role of microRNAs in regulation of BCRP expression and BCRP-mediated drug resistance in breast cancer cells. Microarray analysis was performed to determine the differential expression patterns of miRNAs that target BCRP between the MX-resistant breast cancer cell line MCF-7/MX and its parental MX-sensitive cell line MCF-7. MiR-181a was found to be the most significantly down-regulated miRNA in MCF-7/MX cells. Luciferase activity assay showed that miR-181a mimics inhibited BCRP expression by targeting the 3′ untranslated region (UTR) of the BCRP mRNA. Overexpression of miR-181a down-regulated BCRP expression, and sensitized MX-resistant MCF-7/MX cells to MX. In a nude mouse xenograft model, intratumoral injection of miR-181a mimics inhibited BCRP expression, and enhanced the antitumor activity of MX. In addition, miR-181a inhibitors up-regulated BCRP expression, and rendered MX-sensitive MCF-7 cells resistant to MX. These findings suggest that miR-181a regulates BCRP expression via binding to the 3′-UTR of BCRP mRNA. MiR-181a is critical for regulation of BCRP-mediated resistance to MX. MiR-181a may be a potential target for preventing and reversing drug resistance in breast cancer.

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Acknowledgments

We are grateful to Dr Zhirong Zhan (Molecular Therapeutics Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA) for providing the MCF-7/MX cell. We also greatly appreciate the generous help from Qinghuan Xiao for typing and editing this manuscript. This work was supported by grants from National Natural Science Foundation of China (No. 30973559, No. 81173092), and this study was also supported by Liaoning S&T Projects (No. 2011415052), and Shenyang Technology Projects (No. F11-264-1-19).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, China Medical University, North 2nd Road 92, Heping Ward, Shenyang, 110001, Liaoning, China

    Xuyang Jiao, Lin Zhao, Mengtao Ma, Xuefeng Bai, Miao He, Yuanyuan Yan, Yan Wang, Qiuchen Chen, Xinnan Zhao, Mingyi Zhou & Minjie Wei

  2. Institute of Pathology and Pathophysiology, China Medical University, North 2nd Road 92, Heping Ward, Shenyang, 110001, Liaoning, China

    Zhihong Zheng, Enhua Wang & Minjie Wei

  3. Center of Laboratory Technology and Experimental Medicine, China Medical University, North 2nd Road 92, Heping Ward, Shenyang, 110001, Liaoning, China

    Zeshi Cui

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  1. Xuyang Jiao
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  2. Lin Zhao
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Correspondence to Minjie Wei.

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Xuyang Jiao and Lin Zhao have contributed equally to this work.

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Jiao, X., Zhao, L., Ma, M. et al. MiR-181a enhances drug sensitivity in mitoxantone-resistant breast cancer cells by targeting breast cancer resistance protein (BCRP/ABCG2). Breast Cancer Res Treat 139, 717–730 (2013). https://doi.org/10.1007/s10549-013-2607-x

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