Complex of urokinase-type plasminogen activator with its type 1 inhibitor predicts poor outcome in 576 patients with lymph node-negative breast carcinoma.
BACKGROUND
The ability of a solid tumor to grow and metastasize has a significant dependence on protease systems, such as the plasminogen activation system. The plasminogen activation system includes the urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1), among other molecules. Both uPA and PAI-1 are established prognostic factors for patients with breast carcinoma. In the current study, the authors investigated whether the complex of uPA with PAI-1 is also associated with the natural course of this malignancy.


METHODS
Cytosolic levels of uPA, PAI-1, and the uPA:PAI-1 complex were measured in tumor tissue from 576 patients with lymph node-negative invasive breast carcinoma using quantitative enzyme-linked immunosorbent assays. Patients did not receive adjuvant systemic therapy, and the median follow-up duration was 61 months (range, 2-187 months) after primary diagnosis. Correlations with well known clinicopathologic factors were assessed, and univariate and multivariate survival analyses were performed.


RESULTS
uPA:PAI-1 complex levels were positively associated with adverse histologic grade and inversely correlated with estrogen and progesterone receptor status. On univariate analysis, increased levels of the uPA:PAI-1 complex were found to be associated with reduced recurrence-free survival (RFS) and overall survival (OS) rates. On multivariate analysis, uPA:PAI-1 complex levels were found to be an independent predictor of OS (P = 0.039), but not RFS (P = 0.240). When uPA and PAI-1 levels were not included in the multivariate analysis, uPA:PAI-1 complex levels became a significant predictor of both RFS and OS (P = 0.029 and P = 0.007, respectively).


CONCLUSIONS
The results of the current study demonstrate that uPA:PAI-1 complex levels have prognostic value on univariate analysis. In addition, increased uPA:PAI-1 complex levels were significantly associated with poor OS on multivariate analysis. Increased uPA:PAI-1 complex levels were also significantly associated with reduced RFS rates after the exclusion of uPA and PAI-1 levels from the multivariate analysis model.
Manders
Peggy
P
Department of Chemical Endocrinology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.
Tjan-Heijnen
Vivianne C G
VC
Span
Paul N
PN
Grebenchtchikov
Nicolai
N
Geurts-Moespot
Anneke
A
van Tienoven
Doorlène T H
DT
Beex
Louk V A M
LV
Sweep
Fred C G J
FC
D000328:Adult; D017677:Age Distribution; D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000097:blood; D001707:Biopsy, Needle; D001943:Breast Neoplasms / Q000097:blood* / Q000401:mortality* / Q000473:pathology; D002277:Carcinoma / Q000097:blood* / Q000401:mortality* / Q000473:pathology / Q000556:secondary; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D016019:Survival Analysis; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood
D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator