Inappropriate activation of developmental pathways is a well-recognized
tumor-promoting mechanism. Here we show that overexpression of the
homeoprotein Six1, normally a developmentally restricted transcriptional regulator, increases
TGF-beta signaling in human
breast cancer cells and induces an epithelial-mesenchymal transition (EMT) that is in part dependent on its ability to increase
TGF-beta signaling.
TGF-beta signaling and EMT have been implicated in metastatic dissemination of
carcinoma. Accordingly, we used spontaneous and experimental
metastasis mouse models to demonstrate that Six1 overexpression promotes
breast cancer metastasis. In addition, we show that, like its induction of EMT, Six1-induced experimental
metastasis is dependent on its ability to activate
TGF-beta signaling. Importantly, in human breast
cancers Six1 correlated with nuclear Smad3 and thus increased
TGF-beta signaling. Further,
breast cancer patients whose
tumors overexpressed Six1 had a shortened time to relapse and
metastasis and an overall decrease in survival. Finally, we show that the effects of Six1 on
tumor progression likely extend beyond
breast cancer, since its overexpression correlated with adverse outcomes in numerous other
cancers including brain, cervical, prostate, colon, kidney, and liver. Our findings indicate that Six1, acting through
TGF-beta signaling and EMT, is a powerful and global promoter of
cancer metastasis.