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

摘要

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-beta signaling. The TGF-beta 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-beta signaling from tumor suppressive to tumor promotional. However, the mechanism by which Six1 impinges on the TGF-beta pathway was, until now, unclear. In this work, we identify the TGF-beta type I receptor (TbetaRI) as a target of Six1 and a critical effector of Six1-induced TGF-beta signaling and EMT. We show that Six1-induced upregulation of TbetaRI is both necessary and sufficient to activate TGF-beta signaling and induce properties of EMT. Interestingly, increased TbetaRI expression is not sufficient to induce experimental metastasis, providing in vivo evidence that Six1 overexpression is required to switch TGF-beta 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-beta signaling, identify TbetaRI as a new target of Six1, and implicate Six1 as a determinant of TGF-beta function in breast cancer.