Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

Abstract

We have analysed the pattern of b-catenin expression by immunohistochemistry in mice singly or multiply mutant for Apc, p53 and Msh2. We observed increased expression of b-catenin in all intestinal lesions arising on an Apc Min +/7 background. In all categories of lesion studied mosaic patterns of b-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 bcatenin dysregulation marks pancreatic abnormalities occurring in Apc Min +/7 and (Apc Min +/7, p537/7) mice. In these mice both adenomas and adenocarcinomas of the pancreas arose and were characterized by increased expression of b-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 b-catenin was again observed. However, in contrast with Apc Min +/7 mice, a subset of lesions retained normal expression. Taken together, these ®ndings show that increased expression of b-catenin is an e cient marker of early neoplastic change in both murine intestine and pancreas in Apc mutant mice. However, we also show that dysregulation of b-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.

PPARδ status and Apc-mediated tumourigenesis in the mouse intestine

“…PPARd staining is not present in the smallest detectible (single crypt) lesions in both Apcrecombined tissues and Apc Min mice (Figure 1f), nor in the Apc-deficient tissues ( Figure 1g). In contrast, nuclear localisation of b-catenin is clearly detectable in these lesions (Kongkanuntn et al, 1999) and in the Apcdeficient tissues (Figure 1h). Thus, nuclear accumulation of b-catenin, which occurs at day 3 following the loss of Apc , results in lowered levels of PPARd.…”

The methyl-CpG-binding protein MECP2 is required for prostate cancer cell growth

“…In tumor-prone Apc Min/ þ mice, the methyl-CpG binding protein MBD2 is essential to efficient tumorigenesis in the intestine (Sansom et al, 2003). Interestingly, these mice with a mutated Apc accumulate b-catenin (Kongkanuntn et al, 1999), and the Apc/bcatenin pathway also results in c-myc activation (He et al, 1998). The status of c-myc in Apc…”

MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR

“…In Msh2À/À Mbd4À/À mice, 10% developed intestinal adenomas (2/20) and 90% lymphoma (18/20). When smaller intestinal lesions were microscopically scored and classified according to the morphological criteria (see Kongkanuntn et al, 1999), again there were no differences between genotypes (data not shown). No differences were observed in tumour distribution in the Mlh1-deficient cohorts: Mlh1À/À Mbd4 þ / þ : adenoma 32% (6/19), lymphoma 84% (16/19); Mlh1À/ ÀMbd4 þ /À: adenoma 44% (8/18), lymphoma 66% (12/18); Mlh1À/ÀMbd4À/À: adenoma 30% (6/20), lymphoma 75% (15/20).…”