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 cas cade to mediate remodeling of the extracellular matrix and favor cancer pro gression. Others and the authors of this study recently identified cathepsi n 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 (cathepsi n D) and in situ hybridization (stromelysin-3 and uPA) on formalin fixed pa raffin embedded specimens from 557 breast carcinomas without distant metast asis 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 sign ificantly 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 an y protease expression, irrespective of the type or number of proteases miss ing. Conclusions. This study suggests that proteases expressed by reactive strom al cells are interdependent and that a breach in the protease pathway may i mpair breast carcinoma progression. Cancer 2001;92:2957-64. (C) 2001 Americ an Cancer Society.