Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas

Abstract

Summary It is now clearly established that proteolytic enzymes, including plasminogen activator (uPA), play an important role in breaking down the extracellular matrix, which is considered to be a step in metastasis formation. Plasminogen activators are controlled at various levels. Two inhibitors, PAI-1 and PAI-2, have been identified, the latter being more specific for uPA. In attempts to determine their prognostic value, it is essential to investigate the relative importance of these parameters and their interactions. We used an immunoenzymatic method to assay uPA, PAI-I and PAI-2 antigens in cytosols prepared from 314 primary breast tumours. The patients were followed up for a minimum of 6 years and all relevant clinical and laboratory findings were recorded. Univariate analysis confirmed the poor outcome of patients whose tumours contained large amounts of uPA and PAI-1. In addition, low levels of PAI-2 correlated with shorter disease-free survival in the overall population (P= 0.02), post-menopausal women (P= 0.02) and women without lymph node involvement (P = 0.02). Multivariate analysis in the 'main effects' Cox model identified node involvement, macroscopic tumour size and PAI-2 as significant variables. The 'interactive' model, taking into account interactions between uPA and its two inhibitors, identified a first subgroup with a very poor prognosis associating either high levels of PAI-I with low levels of PAI-2 in the overall population and the women with no node involvement or high levels of uPA with low levels of PAI-2 in the group of menopausal women. We conclude that PAI-I provides the same prognostic information as uPA, and does not appear to play a role as an inhibitor. In contrast, PAI-2 increases the prognostic value of uPA, particularly in post-menopausal women, and PAI-1 in patients with no node involvement.

Prognostic value of urokinase plasminogen activator in primary breast carcinoma: comparison of two immunoassay methods

“…Urokinase and its inhibitors have been proposed as new prognostic factors in breast cancer (Duffy et al, 1990;Janicke et al, 1990;Foekens et al, 1992;Spyratos et al, 1992;Bouchet et al 1994;Foekens et al, 1995). However, their use for this purpose can only be envisaged once the results obtained with different assay methods have been compared.…”

Differential regulation of cell proliferation and protease secretion by epidermal growth factor and amphiregulin in tumoral versus normal breast epithelial cells

“…Many studies have focused on the role of urokinase-type plasminogen activator (uPA) and have described a correlation between uPA expression and cell invasion and metastasis (Foeckens et al, 1992). Type-1 plasminogen activator inhibitor (PAi-1) may also be directly involved in cancer progression, and an increasing number of clinical studies have demonstrated that high PAi-1 levels indicate a poor prognosis for the survival of patients suffering from a variety of cancers (Bouchet et al, 1994).…”

Transforming growth factor beta 1 and sodium butyrate differentially modulate urokinase plasminogen activator and plasminogen activator inhibitor-1 in human breast normal and cancer cells

“…When uPA complexes with PAI-i on the cell surface, it is internalized and degraded in a process mediated by uPA-R (Blasi, 1993). Recently, it was reported that tumour-associated uPA and PAI-I are strong and independent negative prognostic factors for breast cancer patients (Bouchet et al, 1994).…”