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Tumor progression induced by the loss of E-cadherin independent of β-catenin/Tcf-mediated Wnt signaling

Oncogene volume 26, pages 2290–2298 (2007)Cite this article

Abstract

E-cadherin-mediated cell–cell adhesion is frequently lost during the development of malignant epithelial cancers. Employing a transgenic mouse model of β-cell carcinogenesis (Rip1Tag2) we have previously shown that the loss of E-cadherin is a rate-limiting step in the progression from adenoma to carcinoma. However, the mere loss of cell adhesion may not be sufficient and additional signals are required to cause tumor cells to permeate the basal membrane and to invade surrounding tissue. Besides being an important component of the E-cadherin cell-adhesion complex, β-catenin plays a critical role in canonical Wnt signaling. We report here that β-catenin-mediated Wnt signaling does not contribute to tumor progression in Rip1Tag2 mice. E-cadherin downregulates β-catenin/Tcf-mediated transcriptional activity by sequestrating β-catenin into E-cadherin cell-adhesion complexes even in the presence of activated Wnt signaling. Upon loss of E-cadherin expression, β-catenin is degraded and Tcf/β-catenin-mediated transcriptional activity is not induced. Moreover, forced expression of constitutive-active β-catenin or genetic ablation of Tcf/β-catenin transcriptional activity in tumor cells of Rip1Tag2 transgenic mice does not affect tumor progression. Together, the data indicate that signals other than β-catenin/Tcf-mediated Wnt signaling are induced by the loss of E-cadherin during tumor progression in Rip1Tag2 transgenic mice.

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Acknowledgements

We are grateful to P Wilgenbus for technical support. We thank H Clevers and R Kemler for providing important reagents and mice and F Lehembre and A Wicki for critical comments on the manuscript. This work has been supported in part by Boehringer Ingelheim, the Austrian Industrial Research Promotion Fund and the Swedish Cancer Society, Lion's Cancer Research Foundation, Umeå University.

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Author notes

  1. F Savarese

    Present address: Department of Cellular and Molecular Immunology, Max-Planck Institute of Immunobiology, Freiburg, Germany

  2. M Herzig and F Savarese: These authors contributed equally to this work.

Authors and Affiliations

  1. Research Institute of Molecular Pathology, Vienna, Austria

    M Herzig, F Savarese & M Novatchkova

  2. Stem Cell Center, Lund University, Lund, Sweden

    H Semb

  3. Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland

    G Christofori

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  1. M Herzig
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  5. G Christofori
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Correspondence to G Christofori.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Herzig, M., Savarese, F., Novatchkova, M. et al. Tumor progression induced by the loss of E-cadherin independent of β-catenin/Tcf-mediated Wnt signaling. Oncogene 26, 2290–2298 (2007). https://doi.org/10.1038/sj.onc.1210029

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