Homeoprotein Six1 increases TGF-β type I receptor and converts TGF-β signaling from suppressive to supportive for tumor growth

Douglas S. Micalizzi, Chu An Wang, Susan M. Farabaugh, William P. Schiemann, Heide L. Ford

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The Six1 homeodomain protein is a developmental transcription factor that has been implicated in tumor onset and progression. Our recent work shows that Six1 overexpression in human breast cancer cell lines is sufficient to induce epithelial-to-mesenchymal transition (EMT) and metastasis. Importantly, Six1-induced EMT and metastasis are dependent on TGF-β signaling. The TGF-β pathway plays a dual role in cancer, acting as a tumor suppressor in early lesions but enhancing metastatic spread in more advanced tumors. Our previous work indicated that Six1 may be a critical mediator of the switch in TGF-β signaling from tumor suppressive to tumor promotional. However, the mechanism by which Six1 impinges on the TGF-β pathway was, until now, unclear. In this work, we identify the TGF-β type I receptor (TβRI) as a target of Six1 and a critical effector of Six1-induced TGF-β signaling and EMT. We show that Six1-induced upregulation of TβRI is both necessary and sufficient to activate TGF-β signaling and induce properties of EMT. Interestingly, increased TβRI expression is not sufficient to induce experimental metastasis, providing in vivo evidence that Six1 overexpression is required to switch TGF-β signaling to the prometastatic phenotype and showing that induction of EMT is not sufficient to induce experimental metastasis. Together, these results show a novel mechanism for the activation of TGF-β signaling, identify TβRI as a new target of Six1, and implicate Six1 as a determinant of TGF-β function in breast cancer.

Original languageEnglish
Pages (from-to)10371-10380
Number of pages10
JournalCancer Research
Volume70
Issue number24
DOIs
Publication statusPublished - 2010 Dec 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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