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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.

Original publication

DOI

10.15252/embj.201591739

Type

Journal article

Journal

EMBO J

Publication Date

14/09/2015

Volume

34

Pages

2321 - 2333

Keywords

APC, E‐cadherin, colorectal cancer, β‐catenin, Animals, Cadherins, Cell Transformation, Neoplastic, Colonic Neoplasms, Mice, Mice, Transgenic, Mutation, Neoplasm Proteins, Wnt Signaling Pathway, beta Catenin