E-cadherin and adenomatous polyposis coli mutations are synergistic in intestinal tumor initiation in mice

Background & Aims: Inactivation of the adenomatous polyposis coli (APC) gen e is observed at early stages of intestinal tumor formation, whereas loss o f E-cadherin is usually associated with tumor progression, Because both pro teins compete for the binding to beta-catenin, an essential component of th e Wnt signaling pathway, reduction of E-cadherin levels in an Ape mouse mod el could influence both tumor initiation and progression. In addition, loss or haploinsufficiency of E-cadherin may affect tumorigenesis by altering i ts cell-adhesive and associated functions, Methods: Apc1638N mice were bred with animals carrying a targeted E-cadheuin knockout mutation, Results: Do uble heterozygous animals showed a significant B-fold and 5-fold increase o f intestinal and gastric tumor numbers, respectively, compared with Apc1638 N animals. The intestinal tumors of both groups showed no significant diffe rences in grading and staging, Loss of heterozygosity analysis at the Ape a nd E-cadherin loci in both intestinal and gastric Apc(+)/1638N/E-cad(+/-) t umors revealed loss of the wild-type Ape allele in most cases, whereas the wild-type E-cadherin allele was always retained. This was supported by a po sitive, although reduced, staining for E-cadherin of intestinal tumor secti ons. Conclusions: Introduction of the E-cadherin mutation in Apc1638N anima ls enhances Apc-driven tumor initiation without clearly affecting tumor pro gression.