Journal
ONCOGENE
Volume 31, Issue 50, Pages 5162-5171Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.11
Keywords
Six1; miRNA; TGF-beta; epithelial-to-mesenchymal transition; tumor-initiating cell
Funding
- National Cancer Institute [2ROI-CA095277]
- American Cancer Society [RSG-07-183-01-DDC]
- Department of Defense Breast Cancer Research Program [W81XWH-10-1-0296, W81XWH-06-1-0757]
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The role of TGF-beta 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-beta paradox'. Herein, we identify a mechanism by which Six1 activates the tumor promotional arm of TGF-beta 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-beta-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-beta type I receptor and downstream activation of TGF-beta 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-beta 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-beta signaling shifts from tumor suppressive to tumor promoting. Oncogene (2012) 31, 5162-5171; doi:10.1038/onc.2012.11; published online 30 January 2012
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