?-catenin expression in primary and metastatic colorectal carcinoma

Abstract

β-catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also functions in growth signalling events, independently of the cadherin-catenin complex, and these signalling pathways are disturbed in colorectal cancer. Mutations in either the APC or β-catenin genes in colorectal cancer cells result in up-regulation of protein expression and subsequent cytoplasmic and nuclear distribution of β-catenin. In this study, we examined β-catenin expression in 47 primary colorectal tumors and the corresponding liver metastases. Immunohistochemical studies demonstrated loss of membranous β-catenin expression in 26% of primary tumors and 60% of liver metastases and a concomitant increase in cytoplasmic and nuclear staining. Widespread nuclear expression of β-catenin was found in 64% of primary tumors and 21% of liver metastases. No associations were found between any form of β-catenin expression and either tumor stage or tumor grade. Cellular distribution of β-catenin was also examined by detergent extraction and Western blot analysis in 16 primary tumors and 23 liver metastases. This analysis showed that most tumors demonstrated reduced β-catenin in the cytoskeletal fraction and increased β-catenin in the cytosolic fraction. Furthermore, 3 liver metastases were found to contain a truncated β-catenin protein of approximately Mr 80,000. Immunoprecipitation studies showed that the truncated β-catenin proteins only bound weakly to E-cadherin and β-catenin compared with non-truncated β-catenin. These results demonstrate gross alterations in the cellular distribution of β-catenin in primary colorectal cancers with metastatic potential, as well as in the metastatic tumors. These changes may be the consequence of APC or β-catenin gene mutations, or possibly result from a post-translational modification of the E-cadherin-catenin complex. Int. J. Cancer 82:504–511, 1999. © 1999 Wiley-Liss, Inc.