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

Abstract

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 ?-catenin (CTNNB1). We have compared the dynamics and the potency of ?-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of ?-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 ?-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of ?-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:?-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of ?-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of ?-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated ?-catenin. Synopsis In contrast to other Wnt-driven malignancies colorectal cancer is usually linked to APC loss, and very rarely to ?-catenin activating mutations. Different E-cadherin levels can explain the variation in transforming potential of ?-catenin mutations in different tumors. Activating ?-catenin mutations in the mouse small intestine but not the colon lead to Wnt-activation. Increased E-cadherin levels can buffer mutated ?-catenin in the colon epithelium. ?-catenin activating mutations are linked to human cancers that show reduced levels of E-cadherin. In contrast to other Wnt-driven malignancies colorectal cancer is usually linked to APC loss, and very rarely to ?-catenin activating mutations. Different E-cadherin levels can explain the variation in transforming potential of ?-catenin mutations in different tumors. © 2015 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license.