Dysregulated expression of beta-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice.
We have analysed the pattern of beta-catenin expression by immunohistochemistry in mice singly or multiply mutant for Apc, p53 and Msh2. We observed increased expression of beta-catenin in all intestinal lesions arising on an ApcMin+/- background. In all categories of lesion studied mosaic patterns of beta-catenin expression were observed, with the proportion of cells showing enhanced expression decreasing with increasing lesion size. p53 status did not alter these patterns. We also show that beta-catenin dysregulation marks pancreatic abnormalities occurring in ApcMin+/- and (ApcMin+/-, p53-/-) mice. In these mice both adenomas and adenocarcinomas of the pancreas arose and were characterized by increased expression of beta-catenin. We have extended these analyses to intestinal lesions arising in mice mutant for the mismatch repair gene Msh2. In these mice, increased expression of beta-catenin was again observed. However, in contrast with ApcMin+/- mice, a subset of lesions retained normal expression. Taken together, these findings show that increased expression of beta-catenin is an efficient marker of early neoplastic change in both murine intestine and pancreas in Apc mutant mice. However, we also show that dysregulation of beta-catenin is not an obligate step in the development of intestinal lesions, and therefore that genetic events other than the loss of Apc function may initiate the transition from normal to neoplastic epithelium.
Kongkanuntn
R
R
CRC Laboratories, Department of Pathology, University Medical School, Teviot Place, Edinburgh, EH8 9AG, Scotland.
Bubb
V J
VJ
Sansom
O J
OJ
Wyllie
A H
AH
Harrison
D J
DJ
Clarke
A R
AR
D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D015820:Cadherins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D007422:Intestines / Q000473:pathology* / Q000502:physiology; D051379:Mice; D051718:MutS Homolog 2 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein