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Both the Cytosols and Detergent Extracts of Breast Cancer Tissues Are Suited to Evaluate the Prognostic Impact of the Urokinase-Type Plasminogen Activator and Its Inhibitor, Plasminogen Activator Inhibitor Type 1¹

Frauenklinik and Poliklinik [F. J., L. P., M. S., C. T., A. P., H. G.] and Institut für Medizinische Statistik und Epidemiologie [K. U.] der Technischen Universität München, Klinikum rechts der Isar, Ismaningerstrasse 22, D-81675 Munich, Germany

The serine protease urokinase-type plasminogen activator (uPA) plays a key role in tumor-associated proteolysis in malignant solid tumors. Proteolytic activity of uPA is controlled by its naturally occurring plasminogen activator inhibitor type 1. As an initial observation, a correlation of enzymatic uPA activity in breast cancer cytosols with prognosis was described in 1988 (Duffy et al., Cancer (Phila.), 62: 531–533, 1988). A pronounced prognostic impact of uPA, independent of classical risk parameters, was then first demonstrated in detergent-extracted (Triton X-100) breast cancer tissues by applying enzyme-linked immunosorbent assay techniques (Jänicke et al., Lancet, 2: 1049, 1989; Fibrinolysis, 4:69–78, 1990; Duffy et al., Cancer Res., 50: 6827–6829, 1990). In addition, not only uPA but also plasminogen activator inhibitor type 1 were shown to be of prognostic value in breast cancer (Jänicke et al., Semin. Thromb. Hemostasis, 17: 303–312, 1991; Breast Cancer Res. Treat., 24: 195–208, 1993). Subsequently, the prognostic value of uPA and plasminogen activator inhibitor type 1 was also confirmed in studies using archived ‘cytosol fractions" of breast cancer tissues (Foekens et al., Cancer Res., 52: 6101–6105, 1992; Spryatos et al., J. Natl. Cancer Inst., 84: 1266–1272, 1992; Grondahl-Hansen et al., Cancer Res., 53: 2513–2521, 1993; Sumiyoshi et al., Int. J. Cancer, 50: 345–348, 1992). A direct comparison of both methods with regard to prognosis, however, was lacking. We therefore prepared both the detergent-treated tissue extracts and the cytosol fractions from the same breast cancer specimens to allow a direct comparison of both methods.

In 247 breast cancer patients investigated, the Triton X-100-extracted tissues revealed about twice as much uPA antigen (uPA_Tx: median, 2.32 ng/mg protein) than the cytosol fractions (uPA_cyt: median, 1.07 ng/mg protein). In contrast, the presence of Triton X-100 did not result in an increase of PAI-1 (PAI-1_Tx: median, 6.34 ng PAI-1/mg protein) compared to the cytosol fractions (PAI-1_cyt: median, 7.15 ng PAI-1/mg protein). Good correlations between uPA_Tx and uPA_cyt (R = 0.72) and between PAI-1_Tx and PAI-1_cyt (R - 0.88) were observed. Furthermore, PAI-1 and uPA are moderately correlated with each other (uPA_Tx versus PAI-1_Tx: R = 0.40; uPA_cyt versus PAI-1_cyt: R = 0.39). The prognostic power of uPA showed its best advantage in Triton X-100-extracted tissues (RR = 3.22), most pronounced in the subgroups of node-negative and premenopausal patients, respectively. The prognostic value of PAI-1 was not influenced by the extraction procedure (RR = 3.15). As uPA and PAI-1 are both strong independent prognostic parameters (multivariate analysis), simultaneous determination of both factors is recommended to yield optimal prognostic information, preferentially in Triton X-100 extracts.

¹ Supported by the Deutsche Forschungsgemeinschaft (Klinische Forschergruppe GR280/4-1) and the Wilhelm Sander-Stiftung.

Received 10/27/93. Accepted 4/ 5/94.

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