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Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer

Oncogene volume 35, pages 1302–1313 (2016)Cite this article

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Abstract

Acquired therapeutic resistance is the major drawback to effective systemic therapies for cancers. Aggressive triple-negative breast cancers (TNBC) develop resistance to chemotherapies rapidly, whereas the underlying mechanisms are not completely understood. Here we show that genotoxic treatments significantly increased the expression of miR-181a in TNBC cells, which enhanced TNBC cell survival and metastasis upon Doxorubicin treatment. Consistently, high miR-181a level associated with poor disease free survival and overall survival after treatments in breast cancer patients. The upregulation of miR-181a was orchestrated by transcription factor STAT3 whose activation depended on NF-κB-mediated IL-6 induction in TNBC cells upon genotoxic treatment. Intriguingly, activated STAT3 not only directly bound to MIR181A1 promoter to drive transcription but also facilitated the recruitment of MSK1 to the same region where MSK1 promoted a local active chromatin state by phosphorylating histone H3. We further identified BAX as a direct functional target of miR-181a, whose suppression decreased apoptosis and increased invasion of TNBC cells upon Dox treatment. These results were further confirmed by evidence that suppression of miR-181a significantly enhanced therapeutic response and reduced lung metastasis in a TNBC orthotopic model. Collectively, our data suggested that miR-181a induction had a critical role in promoting therapeutic resistance and aggressive behavior of TNBC cells upon genotoxic treatment. Antagonizing miR-181a may serve as a promising strategy to sensitize TNBC cells to chemotherapy and mitigate metastasis.

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Acknowledgements

We thank Dr Bert Vogelstein (Johns Hopkins University) for wild-type and DICER−/− HCT116 cells. The BAX expression construct was a generous gift from Dr Douglas Green (St Jude Children’s Research Hospital). We also thank Dr R. Laribee (UTHSC) for stimulating discussion and critical reading of the manuscript. This work was supported in part by grants from National Cancer Institute (R01 CA149251 to ZW), American Cancer Society (RSG-13-186-01-CSM to ZW), and National Natural Science Foundation of China (NSFC) (81272924 to JW).

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Author notes

  1. J Niu and A Xue: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    J Niu, W Wang, M Fan, C H Yang, L M Pfeffer & Z-H Wu

  2. Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA

    J Niu, Y Chi, W Wang, M Fan, C H Yang, L M Pfeffer & Z-H Wu

  3. Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai, China

    A Xue & Z Zhao

  4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Y Chi, J Xue, Z-M Shao & J Wu

  5. Department of Breast Surgery, Fudan University, Shanghai Cancer Center, Shanghai, China

    Y Chi, J Xue, Z-M Shao & J Wu

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Correspondence to J Wu or Z-H Wu.

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Niu, J., Xue, A., Chi, Y. et al. Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. Oncogene 35, 1302–1313 (2016). https://doi.org/10.1038/onc.2015.189

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