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

Nat Commun. 2020 Feb 7;11(1):785. doi: 10.1038/s41467-020-14556-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition / physiology*
  • Female
  • Gene Expression Regulation
  • Humans
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Mammary Glands, Human / metabolism
  • Mammary Glands, Human / pathology*
  • Mice, SCID
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta