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Tissue Microarray Analysis of ß-Catenin in Colorectal Cancer Shows Nuclear Phospho-ß-catenin Is Associated with a Better Prognosis¹

Department of Internal Medicine, Section Medical Oncology [G. G. C.] and Department of Pathology [E. P., E. P. K., L. A. C., D. L. R.], Yale University School of Medicine, New Haven, Connecticut 06510, and Cell Signaling Technology, Beverly, Massachusetts 01915 [B. L. S.]

Purpose: ß-Catenin is involved in homotypic cell-cell adhesion and the wnt signaling pathway. Deregulation of ß-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 ß-catenin and phosphospecific ß-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 ß-catenin and phosphospecific ß-catenin. These results were correlated with other clinicopathological factors and with overall survival.

Results: The majority of cancers retained some degree of ß-catenin membranous staining, whereas cytoplasmic or nuclear expression was seen in 42.5% and 20.4% of specimens, respectively. Phospho-ß-catenin showed nuclear staining in 9.5% of specimens, and there was no apparent membranous or cytoplasmic staining. There was no significant association between ß-catenin or phospho-ß-catenin and grade or stage. However, there was a positive correlation between ß-catenin and phospho-ß-catenin (P = 0.039), with phospho-ß-catenin representing a subset of nuclear ß-catenin. Patients with nuclear expression of ß-catenin did not have an altered survival compared with those that did not (P = 0.5611). Nuclear expression of phospho-ß-catenin, however, was associated with an improved survival (P = 0.0006). In multivariate analysis, only stage and phospho-ß-catenin were independently predictive of overall survival (P < 0.001 and P = 0.0034, respectively).

Conclusions: These findings support a role for ß-catenin overexpression in colorectal tumorigenesis and provide initial evidence that phospho-ß-catenin may be a marker for improved overall survival independent of stage and grade.

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