Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concentration of total cathepsin D in cytosols of 199 node negative women with primary breast cancer in a 10-year retrospective cohort was assayed. Cathepsin D status alone was unable to predict disease-free or overall survival. However, those patients with receptor positive tumours who were cathepsin D positive had shorter [corrected] disease-free (P = 0.02) and overall survival (P = 0.01) than cathepsin D negative patients. Therefore, measurement of cathepsin D appears to provide additional prognostic information for the prediction of disease-free and overall survival in patients with node negative breast cancer.
Eur J Cancer 1991
PMID:Prognostic relevance of cathepsin D versus oestrogen receptors in node negative breast cancers. 183 5

Current research in the area of breast malignancies is focusing on identification of pathogenetic risk factors, chemoprevention, screening policies, local treatment modalities that minimize disfigurement, and improved adjuvant therapeutic and palliative systemic therapies. Although epidemiologic studies have produced contradictory results, oral contraceptive use before age 25 years and before 1st full-term pregnancy appears to increase the breast cancer risk. In need of thorough study is the safest form of estrogen replacement therapy in postmenopause. Screening programs aimed at early detection have been shown to reduce breast cancer mortality by 30% in women 50-69 years of age, but no preventive strategies have been identified for younger and older women. A trend toward breast-conserving primary therapy represents a major shift in this area. As long as the tumor is less than 4 cm in diameter and the resection margins are free of tumor, lumpectomy produces disease-free survival rates comparable to those obtained through total mastectomy. In node-positive patients, hormonal adjuvant systemic therapy is effective in postmenopausal women while chemotherapy is effective in premenopausal women. The data are insufficient to allow recommendations regarding adjuvant treatment of node-negative patients, whose overall survival rate is about 70%. In metastatic breast cancer, tamoxifen is the drug of choice for palliation. Prognostic factors currently under study include oncogene amplification, urokinase plasminogen activator level, expression of growth factors and growth factor receptors, proliferation parameters, mutations, and cathepsin D levels.
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PMID:Breast malignancy. 187 98

This study, which used combined first-generation prognostic factors (tumor size, histologic differentiation, and age) on 408 patients with axillary node-negative (ANN) breast cancer treated by surgery alone without systemic adjuvant therapy between 1976 and 1987 at the Roswell Park Cancer Institute, discerned four subsets of low-risk patients with a 7-year relapse rate of 6% or better. The first subset consisted of 48 patients (12% of the population) with tumors 1 cm or less in diameter that were well or moderately differentiated. These patients had a disease-free rate (DFR) of 100% (95% confidence interval [CI], 94% to 100%). The second subset consisted of 35 patients (9% of the population) with tumors less than or equal to 1 cm that were poorly differentiated or anaplastic. These patients older than 50 years of age had a DFR of 97% (95% CI, 91% to 100%). The third subset consisted of 36 patients (9% of the population) with tumors 1.1 to 2 cm that were well or moderately differentiated. These patients were older than 50 years of age and had a DFR of 94% (95% CI, 85% to 100%). The fourth subset consisted of 36 patients with ductal carcinoma in situ with microscopic invasion. These patients had a DFR of 100% (95% CI, 87% to 100%). Twenty-two of these patients, not in the other subsets mentioned, comprised 5% of the total population. These patients at low risk of recurrence, who comprise one third of the entire node-negative population, are highly curable by local therapy alone and may be spared the risks and costs of routine adjuvant systemic therapy (AST). Patients with tumors larger than 2 cm (152 patients; 37% of the population) are at high risk of recurrence (26% with a DFR of 74% [95% CI, 64% to 84%]) and should routinely receive systemic adjuvant therapy. Patients with tumors up to 2 cm who are not in the low-risk groups fall in a gray area (recurrence, 15% to 21%; DFR, 79% to 85%). For these groups, combining second-generation prognostic factors such as DNA ploidy, S-phase fraction, or cathepsin D should give the physician additional information to aid in making decisions regarding adjuvant therapy.
Cancer 1991 Oct 01
PMID:Should all patients with node-negative breast cancer receive adjuvant therapy? Identifying additional subsets of low-risk patients who are highly curable by surgery alone. 189 47

The concentrations of cathepsin D (Cath D), urokinase (uPA) and two plasminogen activator inhibitors (PAI-1 and PAI-2) were analysed in the cytosols of 130 human mammary tumours (43 benign tumours and 87 primary and unilateral breast carcinomas). uPA, PAI-1 and PAI-2 levels were measured by antigenic immunoassays and Cath D by immunoradiometric assay. The median levels of the four parameters were significantly higher in the malignant tumours than in the benign ones. Cath D and uPA increases were 4-fold and 5-fold respectively. PAI-1 and PAI-2 increases were much more important, 74-fold and 29-fold respectively. In malignant tumours, median levels of Cath D and uPA did not vary according to classical prognostic factors (histologic grade, presence or absence of axillary lymph nodes, steroid receptors, UICC stage, tumour size, age, and menopausal status). However, PAI-1 decreased in ER+ and PR+ tumours and PAI-2 increased in menopausal women's tumours. When Cath D, uPA, PAI-1 and PAI-2 levels in malignant tumours were compared, positive correlations were found for all combinations. The implication of plasminogen activator inhibitors in the phenomenon was surprising and merits further investigation using tools other than global antigen measurements in tumours.
Br J Cancer 1991 Nov
PMID:Relationship between cathepsin D, urokinase, and plasminogen activator inhibitors in malignant vs benign breast tumours. 193 18

Cathepsin D is a ubiquitously expressed lysosomal protease. Initially synthesized as an inactive precursor of 52 kD (pro-cathepsin D), the enzyme is subsequently converted to its active forms by proteolytic processing. Breast cancer cells, unlike normal cells, secrete high levels of pro-cathepsin D; this abnormal secretion is due to both overexpression of the gene and altered processing of the protein. Recent transfection experiments indicate that overexpression of cathepsin D can increase the metastatic potential of tumor cells in nude mice. This study complements clinical studies, which have shown than high cathepsin D concentrations in the cytosol of primary breast cancers may be predictive of subsequent metastasis, particularly for patients with axillary node-negative tumors. These results, and the potential mechanisms by which cathepsin D may promote metastasis, are considered here.
Cancer Cells 1990 Dec
PMID:Cathepsin D in breast cancer: from molecular and cellular biology to clinical applications. 196 34

Cathepsin D is an acidic lysosomal protease present in all cells. In estrogen receptor positive and negative breast cancer cell lines, the mRNA coding for pro-cathepsin D is overexpressed and sorting and maturation of the pro-enzyme are altered, via possibly saturation of the Man-6-P/IGF-II receptor, leading to accumulation of the active proteinase in large endosomes and to secretion of the precursor (52K protein). In MCF7 cells, the cathepsin D mRNA is induced directly and transcriptionally by estrogens and indirectly by growth factors. In patients, there is a significant correlation between high cathepsin D concentrations in the cytosol of primary breast cancer and development of metastasis. This marker is independent of other prognostic factors and appears to be particularly useful in axillary node-negative tumors. Transfection of a human cDNA cathepsin D expression vector under the control of SV40 promoter increases the metastatic potential of 3YA1-Ad12 rat tumorigenic cells when intravenously injected into nude mice. The mechanism of cathepsin D-induced metastasis is currently unknown. These results indicate that overexpression of cathepsin D might facilitate breast cancer metastasis, suggesting new possible therapeutic approaches.
Cancer Metastasis Rev 1990 Dec
PMID:Cathepsin D: a protease involved in breast cancer metastasis. 196 95

The capacity of solid tumours to invade the surrounding tissue and to metastasize, is correlated with the formation and degradation of structural elements in the vicinity of the tumour cells. Substances with both procoagulant activity and fibrinolytic activity are important factors in the formation or degradation of a "fibrin-fibronectin-gel matrix". This gel is subsequently transformed into the extracellular matrix, which, together with cells, will form the tumour stroma. When analyzing tumour stroma degradation products, it is obvious that the protease plasmin catalyses the disintegration of fibrin and fibronectin. Additional compounds of the tumour stroma and of the basal membrane are also, at least in part, broken down by plasmin or other proteases, such as collagenase IV and cathepsin D. The plasminogen activator urokinase (uPA) seems to play a central role as it was shown that elevated content of uPA is correlated with a high risk of early relapse and shorter overall survival, at least in breast cancer. It has been shown, that by means of quantifying uPA, patients with a relative high or low risk can even be selected within the classical risk groups, which so far are defined by the locoregional extension of the tumour and the hormone receptor status only. Evidently, as uPA content in human breast cancer tissue is an independent prognostic factor, one may speculate, that those experimental or in vitro data, which correlated increase in uPA-synthesis with malignancy, may be of direct relevance for human tumour biology. Moreover, due to these recent observations on the prognostic significance of tumour-associated proteases, new aspects for the selection of risk collectives within the node-negative breast cancer patients for adjuvant therapy have to be considered. It may well be possible, that one may affect tumour invasion and metastasis by inhibiting protease action of solid tumours by disturbing the binding of proteases to tumour cell surface receptors. As it is only a quantitative aspect, which separates benign physiological processes from tumour cell pathophysiology, experimental evidence suggests, that less drastic forms of palliative therapy can be proposed.
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PMID:[Clinical and prognostic significance of tumor-associated proteases in gynecologic oncology]. 204 Apr 18

Cathepsin D is an acidic lysosomal protease present in all cells. In breast cancer cells, pro-cathepsin D expression and secretion are markedly increased and its processing is altered. This protease is induced by estrogens and growth factors. In vitro, pro-cathepsin D is an autocrine mitogen on breast cancer cells and can be auto-activated to degrade extracellular matrix and proteoglycans in acidic microenvironment. In patients, there is a significant correlation between high cathepsin D concentrations in the cytosol of primary breast cancer and development of metastasis. This marker is independent of other prognostic factors and appears to be particularly useful in lymph node-negative tumors. These results suggest that derouting and overexpression of cathepsin D plays an important role in invasion and metastasis of breast cancer cells.
Semin Cancer Biol 1990 Apr
PMID:Biological and clinical significance of cathepsin D in breast cancer. 210 91

Prognostic variables in breast cancer are urgently needed to individualize adjuvant cytotoxic therapy, especially in those patients where metastases in the lymph nodes have not been detected (node-negative disease). So far histomorphological criteria, the determination of receptors for steroid hormones or EGF (epidermal growth factor), the protease cathepsin D or DNA-ploidy are used to distinguish between low- and high-risk patients. High-risk patients have a higher incidence of recurrences and/or shorter overall survival after surgery of the primary tumour than low-risk patients. High-risk patients (node-positive; hormone-receptor-negative) would receive adjuvant hormone therapy or chemotherapy. In the node-negative patient, adjuvant therapy is only recommended if a high content of cathepsin D and aneuploidy of the tumour (or high S-phase in diploid tumours) has been diagnosed. Determination of cathepsin D in tumour extracts as a variable in breast cancer patients is based on the fact that invasion and metastasis is correlated with elevated levels of tumour-associated proteases such as cathepsins B and D, collagenase IV and plasminogen activators. The urokinase-type plasminogen activator (uPA) which is secreted by tumour cells as an enzymatically inactive proenzyme (pro-uPA) seems to play a key role in mediating tumour cell invasion in cancer tissues. Receptor-bound uPA converts enzymatically inactive plasminogen into the serine protease plasmin which then degrades the extracellular matrix surrounding the tumour cells (tumour stroma). We localized pro-uPA/uPA immunohistochemically in paraffin-embedded formalin-fixed breast cancer tissue sections. Pro-uPA/uPA was detected in the cytoplasm and on the plasma membrane of the tumour cells reflecting receptor-bound pro-uPA/uPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumour-associated fibrinolysis: the prognostic relevance of plasminogen activators uPA and tPA in human breast cancer. 213 50

In breast cancer, axillary lymph node invasiveness is the major prognostic factor in predicting relapse and metastasis. Nevertheless, since 30% of node-negative tumors also relapse, it is necessary to develop other independent prognostic factors. Oncogene amplification and the level of cathepsin D (cath-D), an acidic lysosomal protease produced and secreted in excess by breast cancer cells, have been proposed as additional prognostic factors. We have compared the cytosolic cath-D level and the amplification of three oncogenes: c-myc, neu-erb-B-2 and int-2 in 140 primary breast carcinomas and 64 axillary lymph nodes collected in 1987 and 1988 at the Cancer Center of Montpellier (Centre Paul Lamarque). None of the patients had previously received hormonal or chemotherapy. The cath-D concentration was measured with an immunoradiometric assay using monoclonal antibodies. DNA purified from the same samples was analyzed by a standard Southern blotting technique to estimate oncogene amplification. No correlation was found between the level of cath-D in the tumor and node invasiveness. Using a cut-off level of 60 pmol/mg protein, the status of cath-D was not correlated with neu-erb-B-2 and int-2 amplification and only correlated with c-myc amplification (P = 0.011). Both c-myc and cath-D are associated with cell proliferation, induced by estrogens in ER+ breast cancer, and constitutively produced in ER- breast cancer. The level of cath-D was significantly higher in the invaded lymph nodes (P = 0.04) than in the histologically non-invaded ones. Nevertheless, some non-invaded lymph nodes contained a high level of cath-D, as confirmed by immunoperoxidase staining. In conclusion, in breast cancer, a high cytosolic cath-D concentration is more frequent in tumors with c-myc amplification but is dissociated from neu-erb-B-2 or int-2 amplification, suggesting that the determination of these three markers will have an additional prognostic value.
Eur J Cancer 1990 Apr
PMID:Cathepsin D assay in primary breast cancer and lymph nodes: relationship with c-myc, c-erb-B-2 and int-2 oncogene amplification and node invasiveness. 214 10


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