Loss of homotypic cell adhesion is an important prerequisite for invasion and metastasis of epithelial tumor cells. The function of E-cadherin, which mediates epithelial cell-cell adhesion, is regulated by a complex of proteins bound to its cytoplasmic tail, including a-, b-, g-catenins and plakoglobin (PG). The present study was designed to assess whether downregulation of plakoglobin expression occurs in human non-small cell lung carcinomas (NSCLC) and whether this change is associated with an unfavorable prognosis. Using immunohistochemistry with monoclonal antibody (mAb) PG 5.1 to PG, absence or severely reduced expression of PG (i.e., less than 30% of positive tumor cells) was observed in 39 of 97 patients (40.2%) with completely resected primary NSCLC (stages T1-3, N1-2, M0). There was no significant correlation to any of the analyzed clinicopathologic factors such as histologic type, grade or size of the primary tumor, and lymph node involvement. After a median observation period of 39 months (12-56 mo.), univariate Kaplan-Meier analysis showed that patients with PG-deficient primaries tended to have a shortened disease-free survival (p = 0.06). This correlation was statistically significant in patients with adenocarcinomas (p = 0.010), locally restricted primary tumors (pT1/2, p = 0.017), and negative lymph nodes (pN0, p = 0.036). Analysis of the overall survival in these subgroups also revealed significant associations between deficient PG expression and poor outcome (p < or = 0.036). Multivariate analysis was performed for the largest subgroup of patients with pT1/2 tumors (n = 66), demonstrating that PG expression was a strong, independent predictor of tumor relapse (p = 0.002). Thus, deficient expression of PG is a frequent, early event in the progression of NSCLC, which appears to predict an unfavorable prognosis in patients at earlier stages of their disease.