Expression of cathepsin D, stromelysin‐3, and urokinase by reactive stromal cells on breast carcinoma prognosis

BACKGROUND Current literature suggests that several proteases act in a cascade to mediate remodeling of the extracellular matrix and favor cancer progression. Others and the authors of this study recently identified cathepsin D, stromelysin‐3, and urokinase plasminogen activator (uPA) expression by reactive stromal cells as significant factors of poor prognosis in breast carcinoma. The authors evaluated the joint effect of protease expression on cancer aggressiveness. METHODS Protease expression was analyzed by immunohistochemistry (cathepsin D) and in situ hybridization (stromelysin‐3 and uPA) on formalin fixed paraffin embedded specimens from 557 breast carcinomas without distant metastasis at diagnosis and with an average of 10 years of follow‐up. RESULTS Of the 557 breast carcinomas, 80 (14.3%) expressed all 3 proteases, and 134 (24%) expressed none of them. An adjusted Cox model revealed significantly worse distant metastasis free survival (DMFS) with expression of all three proteases (P < 0.0001). The DMFS of patients whose tumor lacked at least one of the three proteases was similar to that of patients without any protease expression, irrespective of the type or number of proteases missing. CONCLUSIONS This study suggests that proteases expressed by reactive stromal cells are interdependent and that a breach in the protease pathway may impair breast carcinoma progression. Cancer 2001;92:2957–64. © 2001 American Cancer Society. Overexpression of cathepsin D, stromelysin‐3, and urokinase plasminogen activator by reactive stromal cells is significantly associated with a poor prognosis in breast carcinoma. This study shows that the survival of patients whose tumor lacked at least one of the three proteases was similar to that of patients without any protease expression, irrespective of the type or number of proteases missing, suggesting that a breach in the protease pathway may impair breast carcinoma progression.