The Expression of Lysosomal Proteinases and Their Inhibitors in Breast Cancer: Possible Relationship to Prognosis of the Disease

Tamara T LAH1, Janko KOS2, Andrej BLEJEC1, Snezana FRKOVIC-GEORGIO3, Rastko GOLOUH3, Ivan VRHOVEC3, Vito TURK2

1Laboratory of Molecular Biology and Biochemistry, National Institute of Biology, Ljubljana, Slovenia
2Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, and KRKA d.d. Ljubljana, Ljubljana, Slovenia
3Departments of Pathology and Clinical Biochemistry, Institute of Oncology, Ljubljana, Slovenia


Proteolytic enzymes have been proposed as new biological prognostic indicators to facilitate decisions about treatment of breast cancer patients following surgery. We reported earlier that the activities of cysteine proteinases (CP), cathepsin (Cat) B and cathepsin (Cat) L and the expression of stefin A might be associated with breast tumor progression and prognosis. Here, the protein concentrations of Cats D, B and L and stefin A have been measured in a series of 60 matched pairs of breast tumours and control adjacent tissues, using ELISAs developed in our laboratory. Median tumor concentrations of Cat D (47 pm/mg), Cat B (222 ng/mg) and Cat L (88 ng/mg) were significantly (p<0.0005) increased by 7 fold, 27 fold and 6 fold, respectively. Much greater increases in the activities of Cat B (63 fold) and of Cat L (274 fold) were found, indicating enhanced activation of cysteine proteinases in tumors, due either to proteolytic activation of proCat B and proCat L and/or to a decrease in specific endogenous cystatins. However, the 1.6-fold decreased (p<0.0001) levels of inhibition by cystatins could not be entirely responsible for more than 100-fold increased ratio of CP:cystatins activity. Moreover, stefin A was either increased or decreased in tumor samples, resulting in a 1.4-fold median increase in tumors. Comparing the biological parameters with the established histo-pathological prognosticators, we found that the increased protein concentration of Cat B was associated with lymph node involvement (p<0.009) and higher stage (p<0.003), and both Cat B and Cat L activities were more increased in high grade tumours (p<0.05). Survival analysis revealed that stefin A was the most significant prognostic factor for disease-free (p<0.008) and overall survival (p<0.02), followed by increased Cat B activity and protein concentration. Cat L was of borderline significance while Cat D was not significant for prognosis. We conclude that enhanced activation of CP, due partially to an imbalance between cysteine proteinases and inhibitors is linked to the progression of breast cancer. Larger sample size is needed to confirm the prognostic significance of stefin A, Cat B and Cat L. Pathology & Oncology Research, Vol 3, Nr 2, 89-99, 1997

Key words: breast cancer; cathepsin B; cathepsin D; cathepsin L; lysosomal enzymes; metastasis; prognostic factors; stefins

Received: May 5, 1997; accepted: Jun 2, 1997
Correspondence: Tamara T LAH, Laboratory of Molecular Biology and Biochemistry, National Institute of Biology, Vecna pot 111 Ljubljana 1000, Slovenia; Tel: 386-61-1233388, Fax: 386-61-1235038; E-mail:

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