Role of urokinase plasminogen activator and plasminogen activator inhibitor mRNA expression as prognostic factors in molecular subtypes of breast cancer

Abstract

Isabell Witzel,1 Karin Milde-Langosch,1 Marcus Schmidt,2 Thomas Karn,3 Sven Becker,3 Ralph Wirtz,4 Achim Rody,5 Elena Laakmann,1 Dina Schütze,1 Fritz Jänicke,1 Volkmar Müller1 1Department of Gynecology, University Medical Center, Hamburg, 2Department of Obstetrics and Gynecology, University Hospital, Mainz, 3Department of Obstetrics and Gynecology, University Hospital, Frankfurt, 4STRATIFYER Molecular Pathology GmbH, Cologne, 5Department of Obstetrics and Gynecology, University Medical Center Schleswig-Holstein, Luebeck, Germany Background: Protein levels of urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) determined by enzyme-linked immunosorbent assay from fresh-frozen tumor tissue have been evaluated as prognostic factors in prospectively randomized trials in breast cancer. However, the role of uPA and PAI-1 in the context of breast cancer subtypes and for mRNA expression of these factors is less clear. Methods: We evaluated uPA and PAI-1 mRNA expression using the Affymetrix HG-U 133A array within molecular subgroups of breast cancer in cohorts of patients with systemic treatment (cohort A, n=362) and without systemic treatment (cohort B, n=200). We validated mRNA expression in a cohort of HER2-positive breast cancer patients (cohort C, n=290). Luminal, triple-negative, and HER2-positive subcohorts were defined by ESR1 and ERBB2 mRNA expression using predefined cutoffs. Results: In the entire cohort A, elevated PAI-1 but not uPA mRNA expression was associated with shorter disease-free survival (P=0.007 for PAI and 0.069 for uPA). Regarding different molecular subgroups, 67% (n=244) of tumors were luminal, 14% (n=49) were HER2-positive, and 19% (n=69) were triple-negative. Elevated PAI-1 mRNA expression was associated with shorter disease-free survival only in the HER2-positive subgroup (P=0.031). The same disease-free survival results were found for uPA in HER2-positive patients (P=0.011). In contrast, no association between either marker and survival was observed in the luminal or triple-negative subgroups. In the HER2-positive validation cohort C, elevated uPA and PAI-1 mRNA expression also showed strong associations with shorter disease-free survival (P=0.014 for PAI-1, P<0.001 for uPA). Conclusion: In this study, the prognostic impact of uPA and PAI-1 expression was mainly observed in patients with HER2-positive tumors. Keywords: urokinase plasminogen activator, urokinase plasminogen activator inhibitor-1, HER2, breast cancer, prognosis