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Based largely on in vitro inve stigations and animal studies, investigators believe that disruptions of transforming growth factor-β (TGF-β) signaling contribute to the development and progression of human colorectal cancer. The purpose of this study was to directly assess the status of the TGF-β signaling pathway in colorectal cancer and determine the effects of its disruption on clinical behavior and outcome.Smad proteins are the principal intracellular components of the TGF-β signaling pathway. We conducted a high-throughput analysis of the expression patterns of Smad2, phosphorylated (activated) Smad2 (pSmad2), and Smad4 in more than 600 human colorectal cancer specimens assembled in tissue microarrays.The vast majority (93.8%; 95% Cl: 92%–96%) of colorectal cancers expressed phosphorylated Smad2, indicating the ability of the tumors to survive and proliferate within a microenvironment that contains bioactive TGF-β. Twelve of 633 (1.9%; 95% Cl: 1%–3%) cases failed to express Smad2, and 15 of 641 (2.3%; 95% Cl: 1%–4%) cases failed to express Smad4. Moreover, 29 of 615 (4.7%; 95% Cl: 3%–7%) of cases expressed Smad2 but not its activated form (pSmad2), suggesting the presence of a TGF-β receptor defect. Based on an analysis of 577 cases for which clinical outcome information was available, failure to express Smad2, pSmad2, or Smad4 was associated with advanced stage disease, the presence of lymph node metastases, and a significantly shorter overall survival (median survival: 35 vs 58 months).Loss of Smad activation and/or expression occurs in approximately 10% of colorectal cancers. This subset has a poor prognosis because of its association with advanced disease and the presence of lymph node metastases at diagnosis.