C/EBPɑ is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition
Lourenço, Ana Rita; Roukens, M. Guy; Seinstra, Danielle; Frederiks, Cynthia L.; Pals, Cornelieke E.; Vervoort, Stephin J.; Margarido, Andreia S.; van Rheenen, Jacco; Coffer, Paul J.
(2020) Nature Communications, volume 11, issue 1, pp. 1 - 18
(Article)
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
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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.
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Keywords: Animals, Breast Neoplasms/genetics, CCAAT-Enhancer-Binding Proteins/genetics, Cells, Cultured, Epithelial Cells/metabolism, Epithelial-Mesenchymal Transition/physiology, Female, Gene Expression Regulation, Humans, Lung Neoplasms/pathology, Mammary Glands, Human/metabolism, Mice, SCID, Smad3 Protein/genetics, Transforming Growth Factor beta/metabolism, Xenograft Model Antitumor Assays, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We would like to thank Prof. Robert A. Weinberg and Dr. Patrick Derksen for providing us the HMLE and MCF10A cells, respectively. A.R.L. was supported by a FCT (Fundação para a Ciência e a Tecnologia) fellowship. A.R.L., S.J.V., M.G.R. and C.L.F. were supported by a grant from the Dutch Cancer Society (KWF). Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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