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MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer

Oncogene volume 39, pages 234–247 (2020)Cite this article

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Abstract

An increased DNA repair capacity is associated with drug resistance and limits the efficacy of chemotherapy in breast cancers. Flap endonuclease 1 (FEN1) participates in various DNA repair pathways and contributes to cancer progression and drug resistance in chemotherapy. Inhibition of FEN1 serves as a potent strategy for cancer therapy. Here, we demonstrate that microRNA-140 (miR-140) inhibits FEN1 expression via directly binding to its 3′ untranslated region, leading to impaired DNA repair and repressed breast cancer progression. Overexpression of miR-140 sensitizes breast cancer cells to chemotherapeutic agents and overcomes drug resistance in breast cancer. Notably, ectopic expression of FEN1 abates the effects of miR-140 on DNA damage and the chemotherapy response in breast cancer cells. Furthermore, the transcription factor/repressor Ying Yang 1 (YY1) directly binds to the miR-140 promoter and activates miR-140 expression, which is attenuated in doxorubicin resistance. Our results demonstrate that miR-140 acts as a tumor suppressor in breast cancer by inhibiting FEN1 to repress DNA damage repair and reveal miR-140 to be a new anti-tumorigenesis factor for adjunctive breast cancer therapy. This novel mechanism will enhance the treatment effect of chemotherapy in breast cancer.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872284, 31400659, and 31701179), China Postdoctoral Science Foundation (2016M591877), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China

    Xiao Lu, Rui Liu, Meina Wang, Alagamuthu Karthick Kumar, Feiyan Pan, Lingfeng He, Zhigang Hu & Zhigang Guo

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  1. Xiao Lu
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Lu, X., Liu, R., Wang, M. et al. MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer. Oncogene 39, 234–247 (2020). https://doi.org/10.1038/s41388-019-0986-0

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