Cell lines:
- Cathepsin D mRNA is expressed at low levels in MCF-7 breast cancer cells (BCC). In these BCC, it is inducible by estradiol. High levels of cathpsin D mRNA, not regulated by estradiol, are found in
ER-negative MDA-MB-231 and BT-20 BCC (Augereau P. et al., 1988).
- Cathepsin D gene transcription in BCC is initiated at multiple sites by a mixed promoter having characteristics of the promoters of both housekeeping and hormonally regulated genes (Cavaillès V. et al., 1993).
- It was concluded that, in contrast to fibroblasts, BCC can endocytose the secreted pro-cathepsin D by a cell surface receptor that is different from the mannose-6-phosphate receptors or other lectins. The nature of this alternative receptor and its significance in the action of secreted pro-cathepsin D remain to be elucidated (Laurent-Matha V. et al., 1998).
- Genistein and quercetin are two well-known phyto-oestrogens. In MCF-7 BCC, genistein promoted transcription of the oestrogen-regulated genes
pS2 and cathepsin-D, whereas quercetin interfered with the oestrogen-induced expression of the proteins. More generally, it was concluded that quercetin acts like a pure anti-oestrogen, whereas genistein displays mixed agonist/antagonist properties in MCF-7 BCC (Miodini P. et al., 1999).
- In BCC, a local reorganization of the chromatin structure over
pS2 and cathepsin D promoters accompanies the establishment of the hormone-independent phenotype of the cells (Giamarchi C. et al., 1999).
Tumors:
- The concentrations of cathepsin D,
uPA,
PAI-1, and
PAI-2 were analysed in the cytosols of 43 benign and 87 malignant mammary tumors. The mean levels of these markers were significantly higher in malignant tumors than in benign tumors. The increases were about 4-, 5-, 74-, and 29-fold, respectively. When cathepsin D,
uPA,
PAI-1, and
PAI-2 levels in malignant tumors were compared, positive correlations were found for all combinations (Foucré D. et al., 1991).
- 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 (Kute T.E. et al., 1998).
- The detection of cathepsin D on breast tumour cells disseminated in bone marrow was found to characterise a subgroup of patients with a poorer prognosis who should undergo more aggressive adjuvant systemic therapy (Solomayer E.F. et al., 1998).
- In a series of 316 primary breast cancers (median follow-up of 77 months), various factors (
PAI-1,
uPA, nodal status, S-phase fraction, cathepsin D, grading, tumor size, hormone receptor status) showed significant univariate impact on disease-free survival (DFS) (Harbeck N. et al., 1999).
- 2810 cytosolic extracts obtained from human primary breast tumours were analysed for cathepsin-D expression, and their levels were correlated with prognosis. The median follow-up of the patients still alive was 88 months. Patients with high cathepsin-D levels had a significantly worse relapse-free and overall survival, also in multivariate analysis (Foekens J.A. et al., 1999).
- 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).
Augereau P. et al. (1988) Cloning and sequencing of the 52K cathepsin D complementary deoxyribonucleic acid of MCF7 breast cancer cells and mapping on chromosome 11. Mol. Endocrinol. 2, 186-192.
Cavaillès V. et al. (1993) Cathepsin D gene is controlled by a mixed promoter, and estrogens stimulate onlt TATA-dependent transcription in breast cancer cells. Proc. Natl. Acad. Sci. USA 90, 203-207.
Faust P.L. et al. (1985) Cloning and sequence analysis of cDNA for human cathepsin D. Proc. Nat. Acad. Sci. 82, 4910-4914.
Foekens J.A. et al. (1999) Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients. Br. J. Cancer 79, 300-307.
Foucré D. et al. (1991) Relationship between cathepsin D,
urokinase, and plasminogen activator inhibitors in malignant
vs benign breast tumours. Br. J. Cancer 64, 926-932.
Giamarchi C. et al. (1999) Chromatin structure of the regulatory regions of
pS2 and cathepsin D genes in hormone-dependent and -independent breast cancer cell lines. Oncogene 18, 533-541.
Harbeck N. et al. (1999b) Invasion marker
PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following first relapse. Breast Cancer Res. Treat. 54, 147-157.
Henry I. et al. (1989) Subregional mapping of BWS, CTSD, MYOD1, and a T-ALL breakpoint in 11p15. (Abstract) Cytogenet. Cell Genet. 51, 1013.
Kute T.E. et al. (1998) Low cathepsin D and low
plasminogen activator type 1 inhibitor in tumor cytosols defines a group of node negative breast cancer patients with low risk of recurrence. Breast Cancer Res. Treat. 47, 9-16.
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.
Laurent-Matha V. et al. (1998) Endocytosis of pro-cathepsin D into breast cancer cells is mostly independent of mannose-6-phosphate receptors. J. Cell Sci. 111, 2539-2549.
Miodini P. et al. (1999) The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. Br. J. Cancer 80, 1150-1155.
Qin S. et al. (1987) Mapping FSHB, CAT, and CTSD to specific sites on 11p. (Abstract) Cytogenet. Cell Genet. 46, 678.
Solomayer E.F. et al. (1998) Prognostic relevance of cathepsin D detection in micrometastatic cells in the bone marrow of patients with primary breast cancer. Breast Cancer Res. Treat. 49, 145-154.
