Tissue Microarray Analysis of -Catenin in Colorectal Cancer Shows Nuclear Phospho- -catenin Is Associated with a Better Prognosis

Purpose: -Catenin is involved in homotypic cell-cell adhesion and the wnt signaling pathway. Deregulation of -catenin levels, caused in part by mutations of the adenomatous polyposis coli gene, is thought to play a role in the development of colorectal and other cancers. To further elucidate their roles, the expression pattern of -catenin and phosphospecific -catenin was correlated with clinical outcome in a series of patients with colorectal cancer. Experimental Design: Immunohistochemical analysis of a tissue microarray with 650 colorectal cancer specimens was performed to study the expression and subcellular localization of -catenin and phosphospecific -catenin. These results were correlated with other clinicopathological factors and with overall survival. Results: The majority of cancers retained some degree of -catenin membranous staining, whereas cytoplasmic or nuclear expression was seen in 42.5% and 20.4% of specimens, respectively. Phospho-catenin showed nuclear staining in 9.5% of specimens, and there was no apparent membranous or cytoplasmic staining. There was no significant association between -catenin or phospho-catenin and grade or stage. However, there was a positive correlation between -catenin and phospho-catenin (P 0.039), with phospho-catenin representing a subset of nuclear -catenin. Patients with nuclear expression of -catenin did not have an altered survival compared with those that did not (P 0.5611). Nuclear expression of phospho-catenin, however, was associated with an improved survival (P 0.0006). In multivariate analysis, only stage and phosphocatenin were independently predictive of overall survival (P < 0.001 and P 0.0034, respectively). Conclusions: These findings support a role for -catenin overexpression in colorectal tumorigenesis and provide initial evidence that phospho-catenin may be a marker for improved overall survival independent of stage and grade.