A variety of serine proteases, including urokinase-type plasminogen
activator (uPA), plasmin,and polymorphonuclear leukocyte elastase (PMN-E),
have been implicated in the processes of tumor cell invasion and
metastasis. Besides degrading of matrix proteins, PMN-E has been shown to
be able to cleave and inactivate plasminogen activator inhibitor-1
(PAI-1), the main inhibitor of uPA, and alpha2-antiplasmin, the natural
inhibitor of plasmin, thus enabling an uncontrolled matrix degradation by
the fibrinolytic enzymes. Because only limited data are available on a
relationship between the tumor level of PMN-E and prognosis in primary
breast cancer patients, in the present study we have measured with an
ELISA the levels of PMN-E (in complex with alpha1-proteinase inhibitor) in
cytosolic extracts of 1143 primary breast tumors. Levels of complexed
PMN-E have been correlated with the lengths of metastasis-free survival
(MFS), relapse-free survival, and overall survival, and a comparison was
made with data previously obtained for uPA and PAI-1. Our results show
that patients with a high PMN-E level in their primary tumor had a rapid
relapse and an early death compared with patients with a low tumor level
of PMN-E. This held true for node-negative and node-positive subgroups of
patients as well. The relationship of PMN-E with a poor prognosis was
especially obvious during short-term follow-up (0-60 months). In Cox
multivariate regression analysis, corrected for the traditional prognostic
factors, PMN-E was an independent prognostic factor, and high levels of
PMN-E were associated with a poor MFS [hazard ratio (HR), 1.63; 95%
confidence interval (CI), 1.23-2.16; P < 0.001], relapse-free survival
(HR, 1.45; 95% CI, 1.10-1.89; P = 0.01), and overall survival (HR, 1.64;
95% CI, 1.20-2.23; P = 0.003). Furthermore, in all three multivariate
models, PMN-E still added significantly to the model after the additional
inclusion of the uPA. PMN-E was an independent prognostic factor for MFS
even in the multivariate analysis including the traditional clinical
prognostic factors and the strong established biochemical prognostic
factors uPA and PAI-1. Our present study suggests that PMN-E is associated
with breast cancer metastasis, and knowledge of the tumor PMN-E status
might be helpful in selecting the appropriate individualized (adjuvant)
treatment for patients with breast cancer