Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer

The Wnt signaling pathway is frequently deranged in colorectal cancer and is a key target for future preventive and therapeutic approaches. Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are characterized by wide-spread microsatellite instability, but show few gross genomic alterations. We characterized expression of the Wnt signaling pathway markers beta-catenin, E-cadherin, TCF-4, and PTEN using immunohistochemical staining in colorectal cancers from individuals with HNPCC. Reduced membranous staining for beta-catenin was found in 64% and for E-cadherin in 80% with strong correlation between these markers (P = 0.001). Nuclear beta-catenin staining was detected in 19% of the tumors. Overexpression of TCF-4, which is activated by beta-catenin, was found in 89% and downregulation of PTEN, which suppresses nuclear accumulation of beta-catenin, was present in 54% of the tumors. In summary, altered expression of target molecules in the Wnt signaling pathway was demonstrated in the vast majority of the HNPCC-associated tumors, which support deranged Wnt-signaling as a central tumorigenic mechanism also in MMR defective colorectal cancer.