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High Levels of Urokinase-type Plasminogen Activator and Its Inhibitor PAI-1 in Cytosolic Extracts of Breast Carcinomas Are Associated with Poor Prognosis¹

Finsen Laboratory, Rigshospitalet, Copenhagen [J. G-H., I. J. C., N. B., K. D.]; Department of Biochemistry and Nutrition, Technical University of Denmark, Lyngby [J. G-H., C. R.]; and Danish Breast Cancer Cooperative Group, Copenhagen [H. T. M., M. B-T.], Denmark

The urokinase pathway of plasminogen activation is supposed to be involved in proteolytic degradation of the extracellular matrix during cancer invasion. The prognostic value of urokinase-type plasminogen activator (uPA) and type 1 plasminogen activator inhibitor (PAI-1) levels in cytosolic extracts of ductal breast carcinomas was studied, retrospectively, in 118 premenopausal and 72 postmenopausal high-risk patients entered into the protocol of Danish Breast Cancer Cooperative Group trials for adjuvant treatment of breast cancer. The median observation time was 8.5 years. uPA and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays. There is a strong correlation between these levels (P < 0.001; r = 0.57). Univariate analysis showed that a high uPA level is significantly associated with short overall survival in both premenopausal (P < 0.001) and postmenopausal (P = 0.03) patients, while a high PAI-1 content significantly predicts shorter overall survival in premenopausal (P = 0.005) and postmenopausal (P < 0.001) patients and shorter relapse-free survival in postmenopausal patients (P < 0.001). When the levels of uPA and PAI-1 are related to those of other prognostic parameters, both high uPA and high PAI-1 levels are associated with grade of anaplasia in premenopausal patients and with number of tumor-positive lymph nodes in postmenopausal patients. A high PAI-1 level is associated with low estrogen and progesterone receptor levels in both pre- and postmenopausal patients. The prognostic value of uPA and PAI-1 levels was compared with that of established prognostic parameters by multivariate analysis. In premenopausal patients, high uPA is an independent prognostic parameter for shorter overall survival, the relative risk being 2.0 (95% confidence interval, 1.1–3.7). In postmenopausal patients, a high PAI-1 level is a strong and independent factor in predicting shorter overall survival with a relative risk of 2.9 (95% confidence interval, 1.5–5.8). In this group of patients a high PAI-1 level is also an independent predictor of shorter relapse-free survival (relative risk, 2.1; 95% confidence interval, 1.1–3.9). These data together with previous reports indicate that uPA and PAI-1 are potentially important prognostic factors in breast cancer. This is in good agreement with the supposed function of uPA in cancer invasion. It is proposed that PAI-1 plays a role in protecting the tumor against degrading itself. Alternatively, the PAI-1 level may be a biochemical marker of tumor angiogenesis.

¹ Supported by the Danish Medical Research Council, the Danish Cancer Society, and the NOVO Foundation.

² To whom requests for reprints should be addressed, at Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, ØDenmark.

Received 11/ 3/92. Accepted 3/29/93.

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