A new conditional Apc-mutant mouse model for colorectal cancer

Abstract

Mutations of the adenomatous polyposis coli (APC) gene predispose individuals to familial adenomatous polyposis (FAP), characterized by multiple tumours in the large intestine. Most mouse models heterozygous for truncating mutant Apc alleles mimic FAP, however, the intestinal tumours occur mainly in the small intestine. To model large intestinal tumours, we generated a new conditional Apc-mutant allele, Apc(15lox), with exon 15 flanked by loxP sites. Similar survival of Apc(1638N/15lox) and Apc(1638N/+) mice indicated that the normal function of Apc was not impaired by the loxP sites. Deletion of exon 15, encoding nearly all functional Apc domains and containing the polyadenylation signal, resulted in a mutant allele expressing low levels of a 74 kDa truncated Apc protein. Germ line Cre-mediated deletion of exon 15 resulted in Apc(Delta15/+) mice, showing a severe Apc(Min/+)-like phenotype characterized by multiple tumours in the small intestine and early lethality. In contrast, conditional Cre-mediated deletion of exon 15 specifically directed to the epithelia of distal small and large intestine of FabplCre;Apc(15lox/+) mice led to longer survival and to tumours that developed predominantly in the large intestine, mimicking human FAP-associated colorectal cancer and sporadic colorectal cancer. We conclude that the FabplCre;Apc(15lox/+) mouse should be an attractive model for studies on prevention and treatment of colorectal cancer.

A mouse model for endometrioid ovarian cancer arising from the distal oviduct

“…1). 23,24 Apc is part of the socalled destruction complex and as such involved in phosphorylation of b-catenin, which marks this protein for degradation. Cre-mediated recombination of Apc destroys the degradation complex, resulting in the stabilization of bcatenin, allowing translocation to the nucleus where it displaces the transcription repressor Groucho (TLE), permitting members of the TCF/LEF transcription factor family to regulate Wnt target gene transcription.…”

“…23 Apc ex15lox mice were developed at our university by Fodde and Smits. 24 Male Pgr Cre/1 mice were bred with female Apc ex15lox/lox mice to eventually obtain Pgr Cre/1 ; Apc ex15lox/lox mice. Pgr Cre/1 mice were used as controls.…”

“…The authors acknowledge Dr. Riccardo Fodde who kindly provided them with the APC ex15lox/lox mice 24 . The funders had no role in study design, data collection and analyses, decision for publication or preparation of the manuscript.…”

Loss of APC function in mesenchymal cells surrounding the Müllerian duct leads to myometrial defects in adult mice

“…Somatic Apc deletion is predicted to result in the constitutive activation of the canonical Wnt pathway and, possibly, in the nuclear accumulation of β-catenin (Gaspar and Fodde, 2004;Robanus-Maandag et al, 2010). However, IHC analysis of β-catenin expression in the uterus of Amhr2 Cre/+ ;Apc 15lox/15lox animals revealed that the majority of myometrial cells are marked by cytoplasmatic β-catenin staining with only few cells showing nuclear staining (Fig.…”

“…Amhr2Cre mice were bred with Rosa26 reporter mice (Soriano, 1999) to review Cre expression, and were bred with Apc 15lox mice (Miclea et al, 2009;Robanus-Maandag et al, 2010) to obtain Apc 15flox/15flox mice ("flox" means that the sequence between two loxP sites has been deleted by Cre). PgrCre animals (Soyal et al, 2005) …”