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miR-155 downregulates ErbB2 and suppresses ErbB2-induced malignant transformation of breast epithelial cells

Oncogene volume 35, pages 6015–6025 (2016)Cite this article

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Abstract

ErbB2 is a vital breast cancer gene and its overexpression has a decisive role in breast tumor initiation and malignant progression. However, the molecular mechanisms that underlie ErbB2 dysregulation in breast cancer cells remain incompletely understood. In this study, we found that ErbB2 expression is inversely correlated with the level of miR-155, a well-documented oncogenic miRNA, in ErbB2-positive breast tumors. We further determined that miR-155 potently suppresses ErbB2 in breast cancer cells. Mechanistically, miR-155 acts to downregulate ErbB2 via two distinct mechanisms. First, miR-155 represses ErbB2 transcription by targeting HDAC2, a transcriptional activator of ErbB2. Second, miR-155 directly targets ErbB2 via a regulatory element in its coding region. Intriguingly, miR-155 is upregulated by trastuzumab and in turn leads to a reduction of ErbB2 expression in trastuzumab-treated ErbB2-positive breast cancer cells. Functional studies showed that miR-155 inhibits ErbB2-induced malignant transformation of human breast epithelial cells. Thus, our findings reveal an intriguing miR-155-ErbB2 context in regulating the malignant transformation of breast epithelial cells, and thereby indicate a novel mode of action for miR-155 in ErbB2-positive breast cancer.

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Acknowledgements

We thank Dr Gao-Xiang Ge for suggestions and critical comments on the manuscript. This work was supported by grants from the Ministry of Science and Technology of China (2012CB910803, 2014CB943103 and 2014CB964802), the National Natural Science Foundation of China (31325008, 91419307, 81502267, and 31300656), the Science and Technology Commission of the Shanghai Municipality (13ZR1464300 and 16XD1404900), and the Chinese Academy of Sciences (KJZD-EW-L01-2 and 2013KIP202) and Foundation of Key Laboratory of Gene Engineering of the Ministry of Education.

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  1. X-H He and W Zhu: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, CAS Center for Excellence in Molecular Cell Science, Shanghai, China

    X-H He, P Yuan, S Jiang & M-F Liu

  2. Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    X-H He, P Yuan, S Jiang & M-F Liu

  3. Department of General Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China

    W Zhu & H-W Zhang

  4. Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    D Li

  5. School of Life Science and Technology, Shanghai Tech University, Shanghai, China

    M-F Liu

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Correspondence to M-F Liu.

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He, XH., Zhu, W., Yuan, P. et al. miR-155 downregulates ErbB2 and suppresses ErbB2-induced malignant transformation of breast epithelial cells. Oncogene 35, 6015–6025 (2016). https://doi.org/10.1038/onc.2016.132

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