title: Role of urokinase plasminogen activator and plasminogen activator inhibitor mRNA expression as prognostic factors in molecular subtypes of breast cancer.
abstract: 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).
  
  
  CONCLUSIONS
  In this study, the prognostic impact of uPA and PAI-1 expression was mainly observed in patients with HER2-positive tumors.
authors.affiliation: Department of Gynecology, University Medical Center, Hamburg, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Witzel
authors.affiliation: Department of Gynecology, University Medical Center, Hamburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Milde-Langosch
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karn
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital, Frankfurt, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Becker
authors.affiliation: STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Wirtz
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center Schleswig-Holstein, Luebeck, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Rody
authors.affiliation: Department of Gynecology, University Medical Center, Hamburg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Laakmann
authors.affiliation: Department of Gynecology, University Medical Center, Hamburg, Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Schütze
authors.affiliation: Department of Gynecology, University Medical Center, Hamburg, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Jänicke
authors.affiliation: Department of Gynecology, University Medical Center, Hamburg, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
keywords: HER2; breast cancer; prognosis; urokinase plasminogen activator; urokinase plasminogen activator inhibitor-1