TY - JOUR
T1 - C/EBPɑ is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition
AU - Lourenço, Ana Rita
AU - Roukens, M. Guy
AU - Seinstra, Danielle
AU - Frederiks, Cynthia L.
AU - Pals, Cornelieke E.
AU - Vervoort, Stephin J.
AU - Margarido, Andreia S.
AU - van Rheenen, Jacco
AU - Coffer, Paul J.
N1 - 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.
PY - 2020/2/7
Y1 - 2020/2/7
N2 - 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.
AB - 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.
KW - Animals
KW - Breast Neoplasms/genetics
KW - CCAAT-Enhancer-Binding Proteins/genetics
KW - Cells, Cultured
KW - Epithelial Cells/metabolism
KW - Epithelial-Mesenchymal Transition/physiology
KW - Female
KW - Gene Expression Regulation
KW - Humans
KW - Lung Neoplasms/pathology
KW - Mammary Glands, Human/metabolism
KW - Mice, SCID
KW - Smad3 Protein/genetics
KW - Transforming Growth Factor beta/metabolism
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=85079083672&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14556-x
DO - 10.1038/s41467-020-14556-x
M3 - Article
C2 - 32034145
AN - SCOPUS:85079083672
SN - 2041-1723
VL - 11
SP - 1
EP - 18
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 785
ER -