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

Ana Rita Lourenço, M. Guy Roukens, Danielle Seinstra, Cynthia L. Frederiks, Cornelieke E. Pals, Stephin J. Vervoort, Andreia S. Margarido, Jacco van Rheenen and Paul J. Coffer ()
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Ana Rita Lourenço: University Medical Center Utrecht
M. Guy Roukens: University Medical Center Utrecht
Danielle Seinstra: Department of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121
Cynthia L. Frederiks: University Medical Center Utrecht
Cornelieke E. Pals: University Medical Center Utrecht
Stephin J. Vervoort: University Medical Center Utrecht
Andreia S. Margarido: Department of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121
Jacco van Rheenen: Department of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121
Paul J. Coffer: University Medical Center Utrecht

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14556-x

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