title: Abnormalities of the cadherin-catenin complex in chemically-induced colo-rectal carcinogenesis.
abstract: Beta-Catenin is a multifunctional protein originally identified as a component of the cadherin cell-cell adhesion complex. It also binds the adenomatous polyposis coli (APC) tumour suppressor which controls beta-catenin cellular levels through its degradation. (beta-Catenin and/or APC mutations result in increased cytoplasmic Beta-catenin and nuclear translocation. The aim of the present study was to examine the expression and cellular localisation of alpha and beta-catenin, p120 and E-cadherin in a chemically-induced mouse model of colo-rectal cancer using 1,2-dimethylhydrazine (DMH). Female Balb/C mice were injected subcutaneously with a solution providing 25 mg DMH base/kg body weight for 17 weeks. Animals were killed and tumours identified in the intestine with a dissecting microscope. Formalin-fixed paraffin-embedded sections of normal and dysplastic colonic mucosa were stained by an indirect avidin-biotin immunohistochemical technique using mouse monoclonal antibodies, and membranous, cytoplasmic and nuclear cellular localisation was assessed by light microscopy. Staining distribution scored as follows: 3, > 90 % positive epithelial cells; 2, >50 % positive epithelial cells; 1, <50 % positive epithelial cells. Non-dysplastic colonic epithelial cells revealed beta-catenin expression at the membrane (33/41 scored 3),areas of cytoplasmic expression (24/41 scored 1) and no nuclear staining. Dysplastic colonic epithelium revealed increased membranous and cytoplasmic, beta-catenin immunoreactivity (39/41 and 38/41 both scored 3) with focal nuclear staining (14/41). Expression patterns for ac-catenin, p120, and E-cadherin were similar to beta-catenin with increased membranous and cytoplasmic immunoreactivity in dysplastic mucosa, although no nuclear staining was observed. Increased cytoplasmic expression and nuclear localisation of beta-catenin are consistent with a possible mutation in its gene, and this finding was in keeping with the mutational analysis of exon 3 by single-strand conformational polymorphism. Increased immunoreactivity of the other catenins also suggests further disruption in catenin regulation. In summary, alterations in the beta-catenin expression and cellular localisation in the DMH-induced tumours are similar to those seen inhuman sporadic colorectal tumours. The DMH is therefore a useful model for studying the abnormalities of the E-cadherin-catenin pathway in colorectal carcinogenesis.
authors.affiliation: University of Bristol, Department of Pathology and Microbiology, School of Medical Sciences and Bristol Royal Infirmary, Bristol, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Tucker
authors.forename: Andrea
authors.initials: A
authors.lastname: Buda
authors.forename: Baker
authors.initials: B
authors.lastname: Janghra
authors.forename: Joy
authors.initials: J
authors.lastname: Cpoad
authors.forename: Morganden
authors.initials: M
authors.lastname: Moorghan
authors.forename: Mike
authors.initials: M
authors.lastname: Havler
authors.forename: Peter
authors.initials: P
authors.lastname: Dettmar
authors.forename: Massimo
authors.initials: M
authors.lastname: Pignatelli
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018807:Polymorphism, Single-Stranded Conformational; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin