Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta 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) 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.
Program in Molecular Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Douglas S
DS
Micalizzi
Chu-An
CA
Wang
Susan M
SM
Farabaugh
William P
WP
Schiemann
Heide L
HL
Ford
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D018398:Homeodomain Proteins; D018125:Receptors, Transforming Growth Factor beta; C099236:SIX1 protein, human; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I