The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression.
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.
Pollard
Patrick
P
Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, England.
Deheragoda
Maesha
M
Segditsas
Stefania
S
Lewis
Annabelle
A
Rowan
Andrew
A
Howarth
Kimberley
K
Willis
Lisa
L
Nye
Emma
E
McCart
Amy
A
Mandir
Nikki
N
Silver
Andrew
A
Goodlad
Robert
R
Stamp
Gordon
G
Cockman
Matthew
M
East
Philip
P
Spencer-Dene
Bradley
B
Poulsom
Richard
R
Wright
Nicholas
N
Tomlinson
Ian
I
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*
D051176:beta Catenin