C/EBPα is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition

Extracellular signals such as TGF-beta can induce epithelial-to-mesenchymal transition (EMT) in cancers of epithelial origin, promoting molecular and phenotypical changes resulting in pro-metastatic characteristics. We identified C/EBP alpha as one of the most TGF-beta-mediated downregulated transcription factors in human mammary epithelial cells. C/EBP alpha expression prevents TGF-beta-driven EMT by inhibiting expression of known EMT factors. Depletion of C/EBP alpha is sufficient to induce mesenchymal-like morphology and molecular features, while cells that had undergone TGF-beta-induced EMT reverted to an epithelial-like state upon C/EBP alpha re-expression. In vivo, mice injected with C/EBP alpha-expressing breast tumor organoids display a dramatic reduction of metastatic lesions. Collectively, our results show that C/EBP alpha is required for maintaining epithelial homeostasis by repressing the expression of key mesenchymal markers, thereby preventing EMT-mediated tumorigenesis. These data suggest that C/EBP alpha is a master epithelial gatekeeper whose expression is required to prevent unwarranted mesenchymal transition, supporting an important role for EMT in mediating breast cancer metastasis.