Abstract
Several signalling pathways contribute to the regulation of epithelial to mesenchymal transition (EMT), either during developmentally regulated processes or in cancer progression and metastasis. Induction of EMT in fully polarized mouse mammary epithelial cells (EpH4) by an inducible c-fos estrogen receptor (FosER) oncoprotein involves loss of E-cadherin expression, nuclear translocation of β-catenin, and autocrine production of TGFβ. Reporter assays demonstrate that both β-catenin/LEF–TCF- and TGFβ–Smad-dependent signalling activities are upregulated, probably coregulating mesenchymal-specific gene expression during EMT. Stable expression of E-cadherin in mesenchymal FosER cells decreased β-catenin activity and reduced cell proliferation. However, these cells still exhibited a defect in epithelial polarization and expressed E-cadherin/β-catenin complexes in the entire plasma membrane. On the other hand, inhibition of TGFβ–Smad signalling in mesenchymal FosER cells induced flat, cobblestone-like clusters of cells, which relocalized β-catenin to the plasma membrane but still lacked detectable E-cadherin. Interestingly, inhibition of TGFβ signalling in the E-cadherin-expressing mesenchymal FosER cells caused their reversion to a polarized epithelial phenotype, in which E-cadherin, β-catenin, and ZO-1 were localized at their correct lateral plasma membrane domains. These results demonstrate that loss of E-cadherin can contribute to increased LEF/TCF-β-catenin signalling, which in turn cooperates with autocrine TGFβ signalling to maintain an undifferentiated mesenchymal phenotype.
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Acknowledgements
We thank Hans Clevers, University Hospital, Utrecht, Netherlands, for providing the TCF-dependent luciferase reporter constructs and Caroline S Hill, Cancer Research Institute, London, UK, for Smad-dependent reporter constructs and Smad expression plasmids. This study was supported by grants from the Austrian Science Research Fund (FWF) No. SFB 006 to RF and HB and from the ‘Hochschuljubiläumsstiftung’of the City of Vienna to AE.
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Eger, A., Stockinger, A., Park, J. et al. β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 23, 2672–2680 (2004). https://doi.org/10.1038/sj.onc.1207416
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DOI: https://doi.org/10.1038/sj.onc.1207416
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