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The Apc1322T Mouse Develops Severe Polyposis Associated With Submaximal Nuclear β-Catenin Expression

2009; Elsevier BV; Volume: 136; Issue: 7 Linguagem: Inglês

10.1053/j.gastro.2009.02.058

1528-0012

Patrick J. Pollard, Maesha Deheragoda, Stefania Segditsas, Annabelle Lewis, Andrew Rowan, Kimberley Howarth, Lisa Willis, Emma Nye, Amy E. McCart Reed, Nikki Mandir, Andrew Silver, Robert A. Goodlad, G. W. H. Stamp, Matthew E. Cockman, Philip East, Bradley Spencer‐Dene, Richard Poulsom, Nicholas A. Wright, Ian Tomlinson,

Genetic factors in colorectal cancer

Background & AimsWe 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 β-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.MethodsWe have constructed a mouse, Apc1322T, 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.ResultsIn 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 β-catenin expression was lower in 1322T than Min tumors.ConclusionsWe propose that the Apc1322T mutation produces submaximal β-catenin levels that promote early tumor growth more effectively than the ApcMin mutation. 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 β-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. We have constructed a mouse, Apc1322T, 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. 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 β-catenin expression was lower in 1322T than Min tumors. We propose that the Apc1322T mutation produces submaximal β-catenin levels that promote early tumor growth more effectively than the ApcMin mutation.