COMBINED OVEREXPRESSION OF UROKINASE, UROKINASE RECEPTOR, AND PLASMINOGEN-ACTIVATOR INHIBITOR-1 IS ASSOCIATED WITH BREAST-CANCER PROGRESSION - AN IMMUNOHISTOCHEMICAL COMPARISON OF NORMAL, BENIGN, AND MALIGNANTBREAST TISSUES

BACKGROUND. A strong positive correlation exists between the breast ca ncer tissue content of either urokinase-plasminogen activator (uPA) or plasminogen activator inhibitor type 1 (PAI-1), quantified in the tis sue extracts by immunoassays, and the survival of patients with breast cancer. Furthermore, several studies assign to the urokinase-type pla sminogen activator receptor (uPAR) a pivotal role in triggering the pr oteolytic activity of the urokinase pathway involved in tumor stroma d egradation, tumor spread and metastasis. However, the pattern of distr ibution of uPAR in normal and cancerous human tissue and the pattern o f coexpression of activators and inhibitors that occurs in breast canc er tissues is not completely known. METHODS. The immunohistochemical l ocalization of uPAR, uPA, tPA) and PAI-1 was evaluated by using the av idin-biotin immunoperoxidase technique and affinity-purified monoclona l antibodies from American Diagnostica Inc. Studies were performed in formalin fixed, paraffin-embedded tissue prepared from 23 surgically e xcised non-neoplastic breast tissues and 18 ductal breast carcinomas. RESULTS. While the expression of uPAR protein represents a constant fe ature of invasive ductal breast cancer, it was also observed in most o f the breast tissue samples, including the normal breast tissues. The staining for uPAR was mainly localized on normal or tumoral epithelial cells, even if the co-expression of uPAR in stromal cells was frequen tly observed in adjacent slides. A semiquantitative analysis of immuno histochemical results showed that uPAR and PAI-1 were overexpressed in invasive breast cancer in comparison with normal and benign breast ti ssues. In addition, uPA was higher in both invasive breast carcinomas and benign breast lesions with respect to normal breast tissues. CONCL USIONS. We showed that overexpression of uPAR, uPA, and its main inhib itor, PAI-1, is a constant feature of invasive ductal breast carcinoma s. However, the expression of the above fibrinolytic reactants is not specific for breast cancer since positive staining for these molecules was frequently observed in benign breast lesions as well as in normal breast tissues. The combined increased expression of uPA and its cell ular receptor, uPAR on the surface of tumor epithelial cells may accou nt for the activation of the proteolytic system which occurs in breast cancer. (C) 1996 American Cancer Society.