E-cadherin can limit the transforming properties of activating β-catenin mutations

• David J Huels ^[6] ; Rachel A Ridgway ^[6] ; Sorina Radulescu ^[6] ; Marc Leushacke ^[1] ; Andrew D Campbell ^[6] ; Sujata Biswas ^[2] ; Simon Leedham ^[2] ; Stefano Serra ^[7] ; Runjan Chetty ^[7] ; Guenievre Moreaux ^[6] ; Lee Parry ^[3] ; James Matthews ^[3] ; Fei Song ^[8] ; Ann Hedley ^[6] ; Gabriela Kalna ^[6] ; Fatih Ceteci ^[6] ; Karen R Reed ^[3] ; Valerie S Meniel ^[3] ; Aoife Maguire ^[9] ; Brendan Doyle ^[10] ; Ola Söderberg ^[4] ; Nick Barker ^[1] ; Alastair Watson ^[5] ; Lionel Larue ^[11] ; Alan R Clarke ^[3] ; Owen J Sansom ^[6]
  1. [1] Institute of Medical Biology

     Institute of Medical Biology

     Singapur

     
  2. [2] Wellcome Trust Centre for Human Genetics

     Wellcome Trust Centre for Human Genetics

     Oxford District, Reino Unido

     
  3. [3] Cardiff University

     Cardiff University

     Castle, Reino Unido

     
  4. [4] Uppsala University

     Uppsala University

     Uppsala domkyrkoförs., Suecia

     
  5. [5] University of East Anglia

     University of East Anglia

     Norwich District, Reino Unido

     
  6. [6] 1 Cancer Research UK Beatson Institute Glasgow, UK
  7. [7] 5 Department of Pathology, University Health Network/Toronto Medical Laboratories Toronto, Canada
  8. [8] 7 Institute of Physiology, Justus-Liebig University Giessen Giessen, Germany
  9. [9] 8 Department of Histopathology, Trinity College Dublin, St James's Hospital Dublin, Ireland
  10. [10] 1 Cancer Research UK Beatson Institute Glasgow, UK; 8 Department of Histopathology, Trinity College Dublin, St James's Hospital Dublin, Ireland
  11. [11] 11 Institut Curie, CNRS UMR3347, INSERM, U1021, Equipe labellisée – Ligue Nationale contre le Cancer Orsay, France

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 18, 2015, págs. 2321-2333
• Idioma: inglés
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  • Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of β-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of β-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated β-catenin.