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

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 b-catenin (CTNNB1). We have compared the dynamics and the potency of b-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of b-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 b-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of b-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin: b-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of b-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of b-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated b-catenin