E-cadherin and adenomatous polyposis coli mutations are synergistic in intestinal tumor initiation in mice.
OBJECTIVE
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 beta-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.
Smits
R
R
Medical Genetics Center, Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Ruiz
P
P
Diaz-Cano
S
S
Luz
A
A
Jagmohan-Changur
S
S
Breukel
C
C
Birchmeier
C
C
Birchmeier
W
W
Fodde
R
R
D025601:Adenomatous Polyposis Coli Protein; D000483:Alleles; D000818:Animals; D015820:Cadherins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D002874:Chromosome Mapping; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology*; D017491:Genes, APC; D006579:Heterozygote; D007413:Intestinal Mucosa / Q000473:pathology*; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins; D003598:Cytoskeletal Proteins