title: The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression.
abstract: OBJECTIVE
  We previously demonstrated that the 2 APC mutations in human colorectal tumors are coselected, because tumorigenesis requires an optimal level of Wnt signaling. We and others subsequently showed that the truncated APC proteins in colorectal tumors usually retain a total of 1-2 beta-catenin binding/degradation repeats (20AARs); very few intestinal tumors have proteins with no 20AARs. The coselection of the "2 hits" at APC makes it difficult to undertake further mechanistic studies in this area in humans. In mice, however, second hits appear to vary with the strain or genetic background used. This suggested the possibility of creating suboptimal Apc genotypes in the mouse.
  
  
  METHODS
  We have constructed a mouse, Apc(1322T), with a mutant protein retaining one 20AAR. After repeated backcrossing to the C57BL/6J background, we compared the 1322T animals with the widely used Min mouse in which the mutant Apc protein has zero 20AARs.
  
  
  RESULTS
  In both mice, intestinal adenomas showed copy-neutral loss of heterozygosity, making them homozygous for the mutant Apc allele. 1322T animals had markedly more severe polyposis, with earlier-onset, larger, more numerous, and more severely dysplastic adenomas. 1322T tumors also had more marked Paneth cell differentiation and higher frequencies of crypt fission. Somewhat surprisingly, nuclear beta-catenin expression was lower in 1322T than Min tumors.
  
  
  CONCLUSIONS
  We propose that the Apc(1322T) mutation produces submaximal beta-catenin levels that promote early tumor growth more effectively than the Apc(Min) mutation.
authors.affiliation: Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, England.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pollard
authors.forename: Maesha
authors.initials: M
authors.lastname: Deheragoda
authors.forename: Stefania
authors.initials: S
authors.lastname: Segditsas
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lewis
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.forename: Lisa
authors.initials: L
authors.lastname: Willis
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.forename: Amy
authors.initials: A
authors.lastname: McCart
authors.forename: Nikki
authors.initials: N
authors.lastname: Mandir
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.forename: Robert
authors.initials: R
authors.lastname: Goodlad
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Matthew
authors.initials: M
authors.lastname: Cockman
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wright
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D019879:Paneth Cells / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051176:beta Catenin