C/EBPɑ is crucial determinant of epithelial homeostasis by preventing epithelial‐to‐mesenchymal transition

Abstract

Extracellular signals such as transforming growth factor beta (TGF‐β) have been shown to influence both tumor initiation and metastasis. TGF‐β has been demonstrated to induce epithelial‐to‐mesenchymal transition (EMT) in cancers of epithelial origin by promoting molecular and phenotypical changes resulting in pro‐metastatic characteristics. Using global RNA‐sequencing analysis, we identified CCAAT/enhancer binding protein alpha (C/EBPα) as one of most TGF‐β‐mediated downregulated transcription factors in human mammary epithelial cells. Here, we show that upon TGF‐β pathway activation, SMAD3 binding to the CEBPA locus is enriched while SMAD3‐knockdown cells fail to repress CEBPA expression. Constitutive C/EBPα expression impaired TGF‐β‐driven EMT by inhibiting the expression of known EMT factors including N‐cadherin, MMP‐2 or ZEB1, and by maintaining E‐cadherin expression. Conversely, depletion of C/EBPα expression alone was sufficient to induce mesenchymal‐like morphology and molecular features. Moreover, cells that had undergone TGF‐β‐induced EMT reverted to an epithelial‐like state upon C/EBPα re‐expression. TGF‐β‐mediated disruption of epithelial spheroids architecture could also be rescued by the introduction of C/EBPα. By using an established mouse model of breast cancer EMT‐driven metastasis, we show that mice injected with tumor organoids constitutively expressing C/EBPα display a dramatic reduction of metastatic lesions in their lungs compared to controls. Taken together, these results show that C/EBPα is required for maintaining epithelial homeostasis by repressing the expression of key mesenchymal markers, thus preventing EMT‐mediated tumorigenesis. These data suggest that C/EBPα is an epithelial “gatekeeper” whose expression is required to prevent unwarranted mesenchymal transition, thereby supporting an important role for EMT in mediating breast cancer metastasis.Support or Funding InformationThis work was supported by a grant from the Dutch Cancer Foundation (KWF).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.