Kute T E, Grøndahl-Hansen J, Shao S M, Long R, Russell G, Brünner N
Department of Pathology, Bowman Gray School of Medicine, Winston-Salem, NC 27157, USA.
Breast Cancer Res Treat. 1998 Jan;47(1):9-16. doi: 10.1023/a:1005882520982.
Prognostic factors are highly needed to divide node negative breast cancer patients into groups of low versus high risk of recurrence and death. In order to invade and spread, cancer cells must degrade extracellular matrix proteins. Accordingly, tumor levels of molecules involved in this degradation might be associated with patient outcome. Previous work has demonstrated that high levels of the aspartyl protease cathepsin D in breast cancer are associated with a poor prognosis and similar findings have been reported for molecules involved in the urokinase pathway of plasminogen activation. Interactions between different protease systems have been described and data suggest that several proteolytic enzymes may be operable at the same time in a tumor. In the present study we measured cathepsin D (n=162), uPA (n=116), uPAR (n=109) and PAI-1 (n=135) in tumor cytosols obtained from a population of node negative breast cancer patients. A significant correlation was found between levels of uPA, uPAR, and PAI-1. Levels of cathepsin D were directly related to levels of uPA and uPAR. With a median observation time of 4.81 years, univariate survival analyses showed that high levels of uPA and cathepsin D significantly predicted a shorter disease free survival, while only high levels of cathepsin D were able to significantly predict a shorter overall survival. Tumor levels of uPAR and PAI-1 gave mixed results depending on the cut-off point chosen. Interestingly, multivariate analysis demonstrated that PAI-1 and cathepsin D were independent significant prognostic indicators for disease-free survival while only cathepsin D was helpful in overall survival. The five year relapse rate of patients with low PAI-1 and low cathepsin D was 13% while patients who had greater than the median value for both of these molecules had a 5 year relapse rate of 40%. These data would indicate that at least two different protease systems are active in spread of node negative breast cancer and that measurement of these molecules may aid in the decisions to be made when offering adjuvant treatment to these patients.
迫切需要预后因素来将淋巴结阴性乳腺癌患者分为复发和死亡风险低与高的组。为了侵袭和扩散，癌细胞必须降解细胞外基质蛋白。因此，参与这种降解的分子的肿瘤水平可能与患者预后相关。先前的研究表明，乳腺癌中天冬氨酰蛋白酶组织蛋白酶D的高水平与预后不良相关，并且对于参与纤溶酶原激活的尿激酶途径的分子也报道了类似的发现。已经描述了不同蛋白酶系统之间的相互作用，并且数据表明几种蛋白水解酶可能在肿瘤中同时起作用。在本研究中，我们测量了从一群淋巴结阴性乳腺癌患者获得的肿瘤细胞溶质中的组织蛋白酶D（n = 162）、尿激酶型纤溶酶原激活物（uPA，n = 116）、尿激酶型纤溶酶原激活物受体（uPAR，n = 109）和纤溶酶原激活物抑制剂-1（PAI-1，n = 135）。发现uPA、uPAR和PAI-1水平之间存在显著相关性。组织蛋白酶D的水平与uPA和uPAR的水平直接相关。中位观察时间为4.81年，单变量生存分析表明，高水平的uPA和组织蛋白酶D显著预测无病生存期较短，而只有高水平的组织蛋白酶D能够显著预测总生存期较短。uPAR和PAI-1的肿瘤水平根据所选的临界值给出了混合结果。有趣的是，多变量分析表明，PAI-1和组织蛋白酶D是无病生存期的独立显著预后指标，而只有组织蛋白酶D对总生存期有帮助。PAI-1和组织蛋白酶D水平低的患者五年复发率为13%，而这两种分子均高于中位数的患者五年复发率为40%。这些数据表明，至少两种不同的蛋白酶系统在淋巴结阴性乳腺癌的扩散中起作用，并且这些分子的测量可能有助于在为这些患者提供辅助治疗时做出决策。
