A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer

Purpose: Cell adhesion molecules are of crucial importance in cancer invasion and metastasis. Epithelial to mesenchymal transition, characterized by reduced E-cadherin and increased N-cadherin expression, has been recognized as a feature of aggressive tumors, but the importance of this phenotype has not been settled in human prostate cancer. We here present novel data, with special focus on the independent relationship between an E-cadherin to N-cadherin switch (EN-switch) and patient prognosis. Experimental Design: Tissue microarray sections from a consecutive series of 104 radical prostatectomies during 1988 to 1994 with detailed clinicopathologic data and long follow-up were studied immunohistochemically for the expression of E-cadherin, N-cadherin, P-cadherin, beta-catenin, and p12(CTN). Results: Low E-cadherin expression was significantly associated with adverse clinicopathologic features, whereas other biomarkers were mostly related to Gleason score. In univariate survival analyses, cadherin switching (high N-cadherin and low E-cadherin) showed strong and significant associations with multiple end points of progression and cancer-specific death. Expression of the "basal cell marker" P-cadherin was associated with shorter time to skeletal metastasis (P = 0.036). In multivariate analysis of time to clinical recurrence, the "EN-switch" (hazard ratio, 4.3; P < 0.0005) had strong and independent prognostic effect, together with Gleason score. Conclusion: These novel data unravel the importance of epithelial to mesenchymal transition for prostate cancer progression, and demonstration of a switch from E-cadherin to N-cadherin expression could have significant effect on the care of prostate cancer patients.