Abstract
Extracellular signals such as TGF-β 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/EBPα as one of the most TGF-β-mediated downregulated transcription factors in human mammary epithelial cells. C/EBPα expression prevents TGF-β-driven EMT by inhibiting expression of known EMT factors. Depletion of C/EBPα is sufficient to induce mesenchymal-like morphology and molecular features, while cells that had undergone TGF-β-induced EMT reverted to an epithelial-like state upon C/EBPα re-expression. In vivo, mice injected with C/EBPα-expressing breast tumor organoids display a dramatic reduction of metastatic lesions. Collectively, our results show that C/EBPα is required for maintaining epithelial homeostasis by repressing the expression of key mesenchymal markers, thereby preventing EMT-mediated tumorigenesis. These data suggest that C/EBPα 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.
Highlights
Extracellular signals such as TGF-β can induce epithelial-to-mesenchymal transition (EMT) in cancers of epithelial origin, promoting molecular and phenotypical changes resulting in prometastatic characteristics
TGF-β signaling can contribute to EMT by inducing gene expression of transcription factors involved in epithelial integrity disruption, and acquisition of mesenchymal traits contributing to cytoskeleton reorganization, extracellular matrix (ECM) remodeling, and cell motility
To identify transcription factors whose expression is repressed by TGF-β, genes displaying significantly reduced expression were analyzed by Gene-Ontology (GO)-term analysis using DAVID
Summary
Extracellular signals such as TGF-β can induce epithelial-to-mesenchymal transition (EMT) in cancers of epithelial origin, promoting molecular and phenotypical changes resulting in prometastatic characteristics. Binding of TGFβ to its cognate receptor results in a multistep phosphorylation cascade of both receptors and key players, the Smad[2] and Smad[3] transcription factors (TFs), where they regulate expression of crucial genes involved in the initiation of the EMT program, including SNAI1, ZEB1, and TWIST17. These transcription factors, known as EMT-TFs, are able to regulate cellular processes, including extracellular matrix remodeling, cell adhesion and migration, and angiogenesis[8]. We identify C/EBPα as a crucial transcription factor in maintaining epithelial architecture of human mammary cells, preventing epithelial-to-mesenchymal transition and thereby acting as a repressor of breast cancer progression in vivo
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