Amyloid precursor protein secretase (APPS) (Tagawa K. et al., 1991)
CTSB (gene locus)
EC 3.4.22.1
Cell lines:
- Cathepsin B activity was found in 4/4 breast cancer cell (BCC) lines investigated (BT-20, MDA-MB-231, PMC42 and T47-D) (Krepela E. et al., 1989).
- The steady state mRNA levels for cathepsin B mRNA was significantly up-regulated in MCF-7 BCC treated with 1,25(OH)
2(D)
3 compared to control cells. Time-dependent increases in the expression of cathepsin B protein was detected by Western blotting in 1,25(OH)
2(D)
3-treated cells (Simboli-Campbell M. et al., 1996).
Tumors:
- Activity of cathepsin B was measured with a fluorometric microtiter plate assay in human breast tumors as well as in mammary gland dysplasias. It was found that primary breast carcinomas and cystosarcomas phyllodes contain significantly higher levels of cathepsin B activity than mammary dysplasias; the activity of cathepsin B in cystosarcomas phyllodes was comparable with that in breast carcinomas. The enzyme from breast carcinoma tissue exhibited properties of a mature form of cathepsin B (Krepela E. et al., 1989).
- Standard immunohistochemical techniques were applied to formalin-fixed, paraffin-embedded tissue to examine the levels of
cathepsins D, B, and L in 80 carcinomas of the breast and compared that with other indicators of aggressive tumor behavior, including stage of disease, tumor size, nuclear grade,
estrogen receptor status, disease recurrence, and 5-year survival rates. Positive granular cytoplasmic staining was detected for
cathepsin D in 90% of the tumors, for cathepsin B in two thirds of the tumors, and for cathepsin L in approximately one half of the tumors. Positive staining also was seen in normal breast epithelium, areas of apocrine metaplasia, stromal fibroblasts, and macrophages. The results did not show a correlation between the expression of
cathepsins D, B, and L and other indicators of aggressive tumor behavior (Castiglioni T. et al., 1994).
- Cathepsin B and cathepsin L levels were determined using ELISA in tumor cytosol fractions of 167 breast cancer patients and in cytosols of 29 benign breast tissue specimens. Median values of 856 ng versus 76 ng cathepsin B/mg protein and of 428 ng versus 56 ng cathepsin L/mg protein were found in tumor versus benign cytosol fractions. A positive correlation between cathepsin B and cathepsin L was found. Cathepsin L was inversely correlated to hormone receptor status and to the presence of tumor necrosis. There were no correlations of cathepsin B or cathepsin L to tumor size, axillary lymph node status, age, menopausal status, tumor grading, and vessel invasion. To perform univariate analyses of disease-free survival, optimal cutoff points were determined by isotonic regression and classification and regression trees analysis. Patients with a high content of cathepsin B (>1092 ng/mg protein) or cathepsin L (>376 ng/mg protein) in their primary tumors had a statistically significantly higher risk of recurrence than patients with a low content of cathepsin B or cathepsin L (5-year disease-free survival: cathepsin B, 70% versus 52%; cathepsin L, 83% versus 52%). Median follow-up was 39 (range, 6-73) months (Thomssen C. et al., 1995).
- Total cathepsin B (catB) was determined by ELISA in 62 specimens of invasive ductal carcinoma of the breast. It was measured in microgram/g of tumour protein (microgram/gtp). The median catB was 91 micrograms/gtp, not varying significantly with T-stage or with age. It was higher in lymph-node negative (143 micrograms/gtp) than in lymph-node positive patients (49 micrograms/gtp), in grade 3 (132 micrograms/gtp) than in grade 1 and 2 tumours (72 micrograms/gtp) and in hormone receptor-negative (155 micrograms/gtp) than in hormone receptor-positive tumours (72 micrograms/gtp). The recurrence-free survival (RFS) at 54 months for patients with tumours with catB < or = 23 micrograms/gtp was 22% and for catB > 23 micrograms/gtp, 68%. CatB > 23 micrograms/gtp did not significantly influence the RFS. Multivariate analysis showed that lymph nodes involvement and catB were independent prognostic factors (Budihna M. et al., 1995).
- Cathepsin B (n = 1,500) and cathepsin L (n = 1,391) levels were determined by enzyme-linked immunosorbent assay (ELISA) in cytosols routinely prepared from frozen-tissue samples. The median duration of follow-up of patients still alive at the time of analysis was 93 months. Relating cathepsin B and cathepsin L levels with classical prognostic factors, the proteases were positively correlated with the number of positive lymph nodes, and negatively with the level of steroid-hormone receptors. We did not find a significant relationship between cathepsin B or cathepsin L levels with age and menopausal status of the patients or with the size of the primary tumor. The levels of cathepsin B and cathepsin L were positively correlated with each other and with the rates of relapse and death. In multivariate regression analysis for relapse-free survival (RFS) and overall survival (OS), corrected for the contribution of age/menopausal status, tumor size, the number of positive lymph nodes, and steroid-hormone-receptor status, cathepsin B and cathepsin L were significant predictors of the rates of relapse and death. No statistically significant interactions of cathepsin B or cathepsin L with any of the classical prognostic factors or with each other were observed in their associations with the rates of relapse and death (Foekens J.A. et al., 1998).
- Cathepsin B (CB) was assayed by ELISA in 193 patients with primary breast cancer. CB levels were significantly higher in both primary and metastatic breast tumors than in fibroadenomas. In the primary carcinomas, CB levels showed no significant correlation with either nodal status, tumor size or estrogen receptor (ER) status. Patients with primary breast cancers containing high levels of CB had a significantly shorter disease-free interval and overall survival than patients with low levels of the protease. However, in multivariate analysis, using nodal status, tumor size,
ER status and
urokinase plasminogen activator (uPA), CB was not an independent prognostic marker. In contrast, nodal status,
ER status and
uPA were prognostic in multivariate analysis. In conclusion, CB, like certain other proteases implicated in cancer metastasis, correlates with poor outcome in patients with breast cancer (Maguire T.M. et al., 1998).
- The activity and protein concentrations of cathepsins (Cats)
D, B, and L were measured in 282 invasive breast tumor cytosols. These potential biological prognostic indicators were compared with other histopathological parameters, such as tumor size, lymph node involvement, tumor-node-metastasis stage, histological grade, DNA analysis, and steroid receptors.
CatD protein concentration correlated with lymph node involvement. CatB and CatL levels correlated significantly with Scarf-Bloom-Richardson histological grade and were also higher in estrogen-negative tumors, and CatB was higher in larger tumors. As prognostic markers, CatB concentration was significant for increased risk for recurrence in the entire patient population and specifically also in lymph node-negative patients as follows: high CatB concentration (above 371 micrograms/g) in tumor cytosols was significant for high risk of recurrence but was of only borderline prognostic significance for overall survival of all patients. In lymph node-negative patients, CatB (above 240 micrograms/g) was highly significant for recurrence-free survival, followed by CatL (above 20 micrograms/g) and
CatD (above 45 nmol/g) concentrations. For overall survival of node-negative patients, only CatB was a significant prognosticator (Lah T.T. et al., 2000).
Budinha M. et al. (1995) Prognostic value of total cathepsin B in invasive ductal carcinoma of the breast. Eur. J. Cancer 31A, 661-664.
Castiglioni T. et al. (1994) Immunohistochemical analysis of
cathepsins D, B, and L in human breast cancer. Hum. Pathol. 25, 857-862.
Chan S.J. et al. (1986) Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs. Proc. Nat. Acad. Sci. USA 83, 7721-7725.
Foekens J.A. et al. (1998) Prognostic significance of cathepsins B and L in primary human breast cancer. J. Clin. Oncol. 1013-1021.
Krepela E. et al. (1989) Cathepsin B in human breast tumor tissue and cancer cells. Neoplasma 36, 41-52.
Lah T.T. et al. (2000) Cathepsin B, a prognostic indicator in lymph node-negative breast carcinoma patients: comparison with
cathepsin D, cathepsin L, and other clinical indicators. Clin. Cancer Res. 6, 578-584.
Maguire T.M. et al. (1998) High levels of cathepsin B predict poor outcome in patients with breast cancer. Int. J. Biol. Markers 13, 139-144.
Simboli-Campbell M. et al. (1996) 1,25-Dihydroxyvitamin D3 induces morphological and biochemical markers of apoptosis in MCF-7 breast cancer cells. J. Steroid Biochem. Mol. Biol. 58, 367-376.
Tagawa K. et al. (1991) Alzheimer's disease amyloid beta-clipping enzyme (APP secretase): identification, purification, and characterization of the enzyme. Biochem. Biophys. Res. Commun. 177, 377-387.
Thomssen C. et al. (1995) Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Clin. Cancer Res. 1, 741-746.
Wang X. et al. (1987) Chromosome assignment of cathepsin B (CTSB) to 8p22 and cathepsin H (CTSH) to 15q24-q25. (Abstract) Cytogenet. Cell Genet. 46, 710-711.
