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

A. L. Smith, R. Iwanaga, D. J. Drasin, D. S. Micalizzi, R. L. Vartuli, Aik-Choon Tan, H. L. Ford

Research output: Contribution to journalArticle

219 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5162-5171
Number of pages10
JournalOncogene
Volume31
Issue number50
DOIs
Publication statusPublished - 2012 Dec 13
Externally publishedYes

Fingerprint

Neoplastic Stem Cells
Breast Neoplasms
Neoplasms
MicroRNAs
Smad7 Protein
Phenotype
Epithelial-Mesenchymal Transition
Carcinogenesis
Up-Regulation
Recurrence
Growth

Keywords

  • epithelial-to-mesenchymal transition
  • miRNA
  • Six1
  • TGF-b
  • tumor-initiating cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

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. / Smith, A. L.; Iwanaga, R.; Drasin, D. J.; Micalizzi, D. S.; Vartuli, R. L.; Tan, Aik-Choon; Ford, H. L.

In: Oncogene, Vol. 31, No. 50, 13.12.2012, p. 5162-5171.

Research output: Contribution to journalArticle

Smith, A. L. ; Iwanaga, R. ; Drasin, D. J. ; Micalizzi, D. S. ; Vartuli, R. L. ; Tan, Aik-Choon ; Ford, H. L. / 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. In: Oncogene. 2012 ; Vol. 31, No. 50. pp. 5162-5171.
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