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

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.

• Authors: Douglas S Micalizzi, Chu-An Wang, Susan M Farabaugh, William P Schiemann, Heide L Ford
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 24 Pg. 10371-80 (Dec 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 21056993 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2010 AACR.

Chemical References

• Homeodomain Proteins
• Receptors, Transforming Growth Factor beta
• SIX1 protein, human
• Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Female
• Gene Expression Regulation, Neoplastic
• Homeodomain Proteins (metabolism)
• Humans
• Mice
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Neoplasm Metastasis
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (biosynthesis, genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (biosynthesis, genetics, metabolism)
• Signal Transduction
• Transcription, Genetic
• Transforming Growth Factor beta (metabolism)
• Up-Regulation