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The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer

Oncogene volume 31, pages 5162–5171 (2012)Cite this article

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Abstract

The role of TGF-β signaling in tumorigenesis is paradoxical: it can be tumor suppressive or tumor promotional, depending on context. The metastatic regulator, Six1, was recently shown to mediate this switch, providing a novel means to explain this elusive ‘TGF-β paradox’. Herein, we identify a mechanism by which Six1 activates the tumor promotional arm of TGF-β signaling, via its ability to upregulate the miR-106b-25 microRNA cluster, and further identify a novel function for this cluster of microRNAs. Although expression of the miR-106b-25 cluster is known to overcome TGF-β-mediated growth suppression via targeting p21 and BIM, we demonstrate for the first time that this same cluster can additionally target the inhibitory Smad7 protein, resulting in increased levels of the TGF-β type I receptor and downstream activation of TGF-β signaling. We further show that the miR-106b-25 cluster is sufficient to induce an epithelial-to-mesenchymal transition and a tumor initiating cell phenotype, and that it is required downstream of Six1 to induce these phenotypes. Finally, we demonstrate a significant correlation between miR-106b, Six1, and activated TGF-β signaling in human breast cancers, and further show that high levels of miR-106b and miR-93 in breast tumors significantly predicts shortened time to relapse. These findings expand the spectrum of oncogenic functions of miR-106b-25, and may provide a novel molecular explanation, through the Six1 regulated miR-106b-25 cluster, by which TGF-β signaling shifts from tumor suppressive to tumor promoting.

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Acknowledgements

The authors acknowledge the strong support of the University of Colorado Cancer Center for use of their core facilities (Flow Cytometry Core and DNA Sequencing and Analysis Core), as well as to the Genomics and Microarray Core at the University of Colorado. We would also like to thank Dr Paul Jedlicka for input and critical reading of the manuscript.

Financial Support: This work was funded by grants from the National Cancer Institute (2ROI-CA095277) and The American Cancer Society (no. RSG-07-183-01-DDC) to HLF. ALS is funded by a predoctoral fellowship from the Department of Defense Breast Cancer Research Program (W81XWH-10-1-0296). DSM was funded by a predoctoral fellowship from the Department of Defense Breast Cancer Research Program (W81XWH-06-1-0757).

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Authors and Affiliations

  1. Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    A L Smith, D J Drasin, D S Micalizzi, R L Vartuli & H L Ford

  2. Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    R Iwanaga & H L Ford

  3. Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    D S Micalizzi & H L Ford

  4. Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    A-C Tan

  5. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    H L Ford

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  1. A L Smith
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Correspondence to H L Ford.

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Smith, A., Iwanaga, R., Drasin, D. et al. The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene 31, 5162–5171 (2012). https://doi.org/10.1038/onc.2012.11

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