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IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG

Oncogene volume 35, pages 1111–1121 (2016)Cite this article

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Abstract

IMP3 (insulin-like growth factor-2 mRNA binding protein 3) is an oncofetal protein whose expression is prognostic for poor outcome in several cancers. Although IMP3 is expressed preferentially in triple-negative breast cancer (TNBC), its function is poorly understood. We observed that IMP3 expression is significantly higher in tumor initiating than in non-tumor initiating breast cancer cells and we demonstrate that IMP3 contributes to self-renewal and tumor initiation, properties associated with cancer stem cells (CSCs). The mechanism by which IMP3 contributes to this phenotype involves its ability to induce the stem cell factor SOX2. IMP3 does not interact with SOX2 mRNA significantly or regulate SOX2 expression directly. We discovered that IMP3 binds avidly to SNAI2 (SLUG) mRNA and regulates its expression by binding to the 5' UTR. This finding is significant because SLUG has been implicated in breast CSCs and TNBC. Moreover, we show that SOX2 is a transcriptional target of SLUG. These data establish a novel mechanism of breast tumor initiation involving IMP3 and they provide a rationale for its association with aggressive disease and poor outcome.

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Acknowledgements

We thank Dr Chung-Cheng Hsieh (University of Massachusetts Medical School) for statistical analysis of our in vivo data. This work was supported by the Megan Lally Memorial Fund and NIH Grants CA168464, CA034196 and AI46629.

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Authors and Affiliations

  1. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester,, MA, USA

    S Samanta, H Sun, H L Goel, B Pursell, C Chang & A M Mercurio

  2. Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA

    A Khan

  3. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    D L Greiner

  4. Dana Farber Cancer Institute, Boston, MA, USA

    S Cao & E Lim

  5. The Jackson Laboratory, Bar Harbor, ME, USA

    L D Shultz

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  1. S Samanta
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Correspondence to A M Mercurio.

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DLG and LDS are consultants for Viacord, Inc. The remaining authors declare no conflict of interest.

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Samanta, S., Sun, H., Goel, H. et al. IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 35, 1111–1121 (2016). https://doi.org/10.1038/onc.2015.164

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