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Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis

Oncogene volume 38, pages 445–453 (2019)Cite this article

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A Correction to this article was published on 30 October 2018

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Abstract

Although it has been demonstrated that transformed progenitor cell population can contribute to tumor initiation, factors contributing to this malignant transformation are poorly known. Using in vitro and xenograft-based models, previous studies demonstrated that miR-489 acts as a tumor suppressor miRNA by targeting various oncogenic pathways. It has been demonstrated that miR-489 directly targets HER2 and inhibits the HER2 signaling pathway; however, its role in mammary gland development and HER2-induced tumor initiation hasn’t been studied. To dissect the role of miR-489, we sorted different populations of mammary epithelial cells and determined that miR-489 was highly expressed in mammary stem cells. MMTV-miR-489 mice that overexpressed miR-489 in mammary epithelial cells were developed and these mice exhibited an inhibition of mammary gland development in early ages with a specific impact on highly proliferative cells. Double transgenic MMTV-Her2-miR489 mice were then generated to observe how miR-489 overexpression affects HER2-induced tumorigenesis. miR-489 overexpression delayed HER2-induced tumor initiation significantly. Moreover, miR-489 overexpression inhibited tumor growth and lung metastasis. miR-489 overexpression reduced mammary progenitor cell population significantly in preneoplastic mammary glands of MMTV-Her2 mice which showed a putative transformed population in HER2-induced tumorigenesis. The miR-489 overexpression reduced CD49fhiCD61hi populations in tumors that have stem-like properties, and miR-489 overexpression altered the HER2 signaling pathway in mammary tumors. Altogether, these data indicate that the inhibition of HER2-induced tumorigenesis by miR-489 overexpression was due to altering progenitor cell populations while decreasing tumor growth and metastasis via influencing tumor promoting genes DEK and SHP2.

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  • 30 October 2018

    In the published version of this paper the author A. Awgulewitsch’s surname was incorrectly given as Awagulerwitsch instead of Awgulewitsch. This has now been corrected in the HTML version of the paper, the PDF was correct at the time of publication.

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Acknowledgements

We would like to thank the Gene Function and Transgenic and Genome Editing (TGE) Cores of the Medical University of South Carolina (MUSC) for their assistance with the generation of transgenic MMTV-miR-489 mice. This work was supported by the NIH grants (4R01 CA178386-04 and 4P30 GM103342-05) and the USC ASPIRE-1 grant to H.C., and the USC SPARC graduate research grant to M.S.

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Authors and Affiliations

  1. Department of Biological Science, University of South Carolina, Columbia, SC, 29208, USA

    Y. Patel, M. Soni, S. Liu, N. Shah & H. Chen

  2. Center for Colon Cancer Research, University of South Carolina, Columbia, SC, 29208, USA

    Y. Patel, M. Soni, S. Liu, N. Shah & H. Chen

  3. Department of Medicine and Department of Regenerative Medicine and Cell Biology, Transgenic and Genome Editing Core, Medical University of South Carolina (MUSC), Charleston, SC, 29425, USA

    A. Awgulewitsch

  4. Department of Regenerative Medicine and Cell Biology, Director, Gene Function Core, Medical University of South Carolina, Charleston, SC, 29425, USA

    M. J. Kern

  5. Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, 29208, USA

    U. P. Singh

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Correspondence to H. Chen.

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Patel, Y., Soni, M., Awgulewitsch, A. et al. Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis. Oncogene 38, 445–453 (2019). https://doi.org/10.1038/s41388-018-0439-1

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