Tumor and Stem Cell Biology Homeoprotein Six1 Increases TGF-b Type I Receptor and Converts TGF-b Signaling from Suppressive to Supportive for Tumor Growth

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) andmetastasis. Importantly, Six1-induced EMT and metastasis are dependent on TGF-b signaling. The TGF-b pathway plays a dual role in cancer, acting as a tumor suppressor in early lesions but enhancing metastatic spread inmore advanced tumors. Our previous work indicated that Six1 may be a critical mediator of the switch in TGF-b signaling from tumor suppressive to tumor promotional. However, the mechanism by which Six1 impinges on the TGF-b pathway was, until now, unclear. In this work, we identify the TGF-b type I receptor (TbRI) as a target of Six1 and a critical effector of Six1-induced TGF-b signaling and EMT. We show that Six1-induced upregulation of TbRI is both necessary and sufficient to activate TGF-b signaling and induce properties of EMT. Interestingly, increased TbRI expression is not sufficient to induce experimental metastasis, providing in vivo evidence that Six1 overexpression is required to switch TGF-b 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-b signaling, identify TbRI as a new target of Six1, and implicate Six1 as a determinant of TGF-b function in breast cancer. Cancer Res; 70(24); 10371–80. 2010 AACR.