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

Ron Smits, Patricia Ruiz, Salvador Diaz-Cano, Arne Luz, Shantie Jagmohan-Changur, Cor Breukel, Carmen Birchmeier, Walter Birchmeier, Riccardo Fodde

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Scopus)

Abstract

Background and Aims: Inactivation of the adenomatous polyposis coli (APC) gene is observed at early stages of intestinal tumor formation, whereas loss of E-cadherin is usually associated with tumor progression. Because both proteins compete for the binding to β-catenin, an essential component of the Wnt signaling pathway, reduction of E-cadherin levels in an Apc mouse model could influence both tumor initiation and progression. In addition, loss or haploinsufficiency of E-cadherin may affect tumorigenesis by altering its cell-adhesive and associated functions. Methods: Apc1638N mice were bred with animals carrying a targeted E-cadherin knockout mutation. Results: Double heterozygous animals showed a significant 9-fold and 5-fold increase of intestinal and gastric tumor numbers, respectively, compared with Apc1638N animals. The intestinal tumors of both groups showed no significant differences in grading and staging. Loss of heterozygosity analysis at the Apc and E-cadherin loci in both intestinal and gastric Apc+/(1638N)/E-cad+/- tumors revealed loss of the wild-type Apc allele in most cases, whereas the wild-type E-cadherin allele was always retained. This was supported by a positive, although reduced, staining for E-cadherin of intestinal tumor sections. Conclusions: Introduction of the E-cadherin mutation in Apc1638N animals enhances Apc-driven tumor initiation without clearly affecting tumor progression.

Original languageEnglish
Pages (from-to)1045-1053
Number of pages9
JournalGastroenterology
Volume119
Issue number4
DOIs
Publication statusPublished - 2000

Bibliographical note

Funding Information:
Supported by grants from the Dutch Cancer Society (94-817, to R.S; C.B., 95-1102, to S.J.-C.); a fellowship from the European Union (P.R.); the Deutsche Krebshilfe (to W.B.); and the Dutch Royal Academy of Sciences (to R.F.).

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