Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 Mr 52,000 cathepsin D is the precursor of a lysosomal protease secreted in excess by breast cancer cells. This protease can degrade extracellular matrices and proteoglycans and is induced by estrogens in estrogen receptor-positive breast cancer cell lines. In a 4- to 6-yr retrospective cohort study, the concentration of the total cathepsin D (precursor plus intermediate and mature chains) was assayed in cytosols of primary tumors from 242 pre/perimenopausal and 154 postmenopausal breast cancer patients in a solid-phase immunoassay using two specific monoclonal antibodies. Patients were initially divided into groups with low, intermediate, or high concentrations of cathepsin D corresponding to the quartiles of the overall distribution. Using these groupings, the level of Mr 52,000 cathepsin D was not significantly associated with the recognized prognostic factors of age, lymph node involvement, tumor size, and/or grade of anaplasia. A significant association was found between cathepsin D concentrations and estrogen receptor status only among pre/perimenopausal patients. Receptor-positive tumors (greater than or equal to 10 fmol of estrogen receptor/mg of cytosol protein) had a significantly greater proportion of patients with high Mr 52,000 cathepsin D concentrations. Patients with high Mr 52,000 cathepsin D concentrations (greater than 78 pmol/mg for pre/perimenopausal and greater than 24 for postmenopausal patients) have shorter recurrence-free survival (P = 0.06 for pre/peri- and P = 0.039 for postmenopausal patients) and have a trend toward shorter overall survival (P = 0.30 and P = 0.089 for pre/peri- and postmenopausal groups, respectively). In multivariate analysis, Mr 52,000 cathepsin D status was found to be an independent prognostic factor for recurrence-free survival of about the same import as lymph node status for both menopausal groups. This first retrospective study demonstrates that the level of Mr 52,000 cathepsin D in cytosol of primary breast cancer biopsies is an independent prognostic factor in predicting relapses in both pre/peri- and postmenopausal patients.
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PMID:Association between high concentrations of Mr 52,000 cathepsin D and poor prognosis in primary human breast cancer. 279 Aug 15

The pro-cathepsin D of Mr 52,000 is regulated by estrogens via the estrogen receptor (RE) and is secreted by breast cancer cells in vitro. In an attempt to predict the hormone responsiveness of breast cancer in vivo, we have assayed total 52K cathepsin D and its precursor in the primary breast cancer cytosol of 36 patients treated before surgery with 30 mg of tamoxifen daily for 1 to 5 weeks (average, 3 weeks). Compared to a similar control population, total 52K cathepsin D was increased by tamoxifen (P = 0.02) but less so than its precursor (P less than 0.001). Furthermore, 45% of the RE-positive tumors from tamoxifen-treated patients had a higher cathepsin D precursor concentration than the same type of tumor from control patients, or than RE-negative tumors from tamoxifen-treated patients. This 3-week challenge test was probably too short to avoid partial estrogenic activity of tamoxifen (flare) and the authors infer that longer time of treatment would decrease rather than increase the concentration of cathepsin D in the RE-responsive tumors. However, two cancers from patients with relapses after prolonged tamoxifen treatment (greater than 6 months) also had high concentrations of 52K cathepsin D and its precursor. The authors conclude that the concentration of cathepsin D and its precursor in breast cancer cytosol can be increased by short-term tamoxifen treatment, suggesting that these tumors are estrogen responsive.
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PMID:Tamoxifen treatment increases the concentration of 52K-cathepsin D and its precursor in breast cancer tissue. 292 Mar 55

The Mr 52,000 cathepsin-D-like protease induced by estrogens in MCF7 human breast cells was assayed in 182 primary breast cancer cytosols prepared for receptor assays from pre- and post-menopausal patients. Using two solid-phase sandwich immunoenzymatic assays, we quantified the total Mr 52,000 cathepsin D (52K-cath-D) (the Mr 52,000 precursor protein and its Mr 48,000 and 34,000 processed forms) and the Mr 52,000 precursor alone. The value of total 52K-cath-D varied between 3 and 165 pmol/mg protein and the proportion of the precursor varied from 0 to 28% of total 52K-cath-D. There was no correlation between the concentrations of 52K-cath-D and estrogen receptor, but the estrogen receptor status (greater than or less than 10 fmol/mg protein) was correlated to the 52K-cath-D status (greater than or less than 15 pmol/mg protein) according to the chi 2 test (P less than 0.001). The correlation with progesterone receptor concentrations and status was low (r = 0.43) and absent, respectively. There was no correlation with Scarff and Bloom stages, tumor size, or patient's age. The percentage of patients with invaded lymph nodes was significantly higher (80%) in the subgroup with the highest total 52K-cath-D levels (greater than or equal to 42 pmol/mg protein), representing only 12% of the population but not in the total population. On the basis of this prospective study, before clinical follow-up can be evaluated, we conclude that in the total population examined, the 52K-cath-D concentration was only correlated with estrogen receptor status, but not with any other prognostic parameter.
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PMID:Immunoenzymatic assay of Mr 52,000 cathepsin D in 182 breast cancer cytosols: low correlation with other prognostic parameters. 327 97

It has been proposed that proteases secreted by cancer cells facilitate metastasis by degrading extracellular matrix. Estrogen receptor-positive breast cancer cells secrete a Mr 52,000 pro-cath-D under estrogen stimulation, whereas this protease is produced constitutively by estrogen receptor-negative cancer cells. We report on the degradation in vitro of extracellular matrix by purified Mr 52,000 cathepsin D (cath-D) and by conditioned media prepared from different cell lines. The purified Mr 52,000 pro-cath-D was autoactivated at pH 4.5 into a Mr 51,000 cath-D and found to digest the extracellular matrix of endothelial bovine corneal cells labeled with [3H]proline or [35S]methionine. Culture medium conditioned by estrogen-treated MCF7 cells had a similar effect at pH 4.5 but not at pH 7.4. Matrix degradation was totally inhibited by pepstatin. Other breast cancer cells (BT20, MDA-MB231, T47D cells, etc.) and other cancer cells also secreted a pepstatin-sensitive proteinase able to degrade extracellular matrix. By contrast, the U2 variant of MCF7 cells, which lacks the Mr 52,000 cath-D gene, and the nontumoral epithelial mammary cells secreted a negligible amount of this proteinase. In all conditioned media, the pepstatin-dependent extracellular matrix degrading activity was highly correlated to the Mr 52,000 cath-D concentration measured by immunoenzymatic assay. We conclude that the Mr 52,000 cath-D is the major acidic protease secreted by mammary cancer cells. We suggest that this protease may degrade basement membrane and consequently facilitate tumor invasion when it is released in an acidic microenvironment.
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PMID:In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells. 337 11

The aryl hydrocarbon (Ah) receptor binds several different structural classes of chemicals, including halogenated aromatics, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polynuclear aromatic and heteropolynuclear aromatic hydrocarbons. TCDD induces expression of several genes including CYP1A1, and molecular biology studies show that the Ah receptor acts as a nuclear ligand-induced transcription factor that interacts with xenobiotic or dioxin responsive elements located in 5'-flanking regions of responsive genes. TCDD also elicits diverse toxic effects, modulates endocrine pathways and inhibits a broad spectrum of estrogen (17 beta-estradiol)-induced responses in rodents and human breast cancer cell lines. Molecular biology studies show that TCDD inhibited 17 beta-estradiol-induced cathepsin D gene expression by targeted interaction of the nuclear Ah receptor with imperfect dioxin responsive elements strategically located within the estrogen receptor-Sp1 enhancer sequence of this gene.
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PMID:Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. 749 65

Insulin-like growth factor-binding protein-3 (IG-FBP-3) is an important member of a family of proteins which binds IGF peptides and modulates their biological actions. In this study, we describe an acid-activated IGFBP-3 protease in media derived from a variety of human cell lines. Radiolabeled IGFBP-3 remained intact during incubation (pH 5.5-8) in media conditioned by normal and transformed human fibroblasts, MG-63 osteoblastic cells, and breast cancer cell lines MCF-7 and Hs578T. However, acidification of the conditioned medium samples (pH < 5.5) resulted in 125I-IGFBP-3 hydrolysis and the appearance of specific radiolabeled fragments. No proteolysis of 125I-IGFBP-3 occurred during incubation in unconditioned medium at neutral or acid pH. Estrogen treatment of estrogen receptor-positive MCF-7 cells enhanced acid-activatable IGFBP-3 proteolysis in the cell-conditioned medium but had no effect on proteolytic activity in estrogen receptor-negative Hs578T cells. The cell-derived IGFBP-3 protease was identified as the aspartic proteinase cathepsin D, based on acidic pH optimum, inhibition by pepstatin, distinctive proteolytic fragment pattern, and immunoreactivity with cathepsin D antisera. Furthermore, immuno-depletion of cathepsin D effectively attenuated acid-activated IGFBP-3 proteolysis. These data suggest a role for cathepsin D in the regulation of cellular IGF action by virtue of its potential to alter the structure/function of IGFBP-3.
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PMID:Acid-activated insulin-like growth factor-binding protein-3 proteolysis in normal and transformed cells. Role of cathepsin D. 751 Feb 81

We made an effort to identify a reliable source for obtaining large quantities of both free (PSA) and PSA-ACT complex for the preparation of the calibrator for the PSA assay. Using size exclusion chromatography, we found both free PSA and PSA-ACT complex in the conditioned cell medium of the LNCaP cell line, which was derived from a human metastatic adenocarcinoma of the prostate. An assay specific for PSA-ACT reacted only with the PSA-ACT complex from cells grown in serum-free medium, and not with the complex from the cell medium grown in 10% calf serum. We also found both free PSA and PSA-ACT complex in 15% of cytosols prepared from breast tumor tissues; the cytosol PSA concentrations ranged from 0.1 to 110 ng/ml. No correlation was found between cytosol PSA and concentrations of estrogen receptor, progestin receptor, epidermal growth factor receptor, cathepsin D, or the ectodomain of c-erbB-2 protein. Based on chromatographic characterizations and the slope of their dose-response curves, it appears that both free PSA and PSA-ACT complex found in the cytosols are similar to PSA complex from the cell medium and the serum of prostate cancer patients. Ectopic PSA was also detected in pooled sera from patients with breast, ovarian, pancreatic, and colon carcinoma. The PSA concentrations in these serum pools increased with the level of their dominant tumor marker. In any event, the LNCaP cell medium appears to be a reliable source for obtaining both free and ACT-complexed PSA of human tumor origin for the preparation of PSA assay calibrators.
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PMID:PSA immunoreactivity detected in LNCaP cell medium, breast tumor cytosol, and female serum. 756 42

We evaluated cathepsin D concentrations in 318 breast carcinoma specimens with a standardized IRMA and established distribution values of 5.9-217.8 nmol/g (median 51.8). Concentrations of cathepsin D did not correlate with age or with concentrations of HER-2/neu oncoprotein, estrogen receptor, or epidermal growth factor receptors. A significant correlation was observed between cathepsin D and progestin receptor (P = 0.009), but only in postmenopausal patients. In our role as a National Reference Laboratory for conducting interlaboratory comparisons of tumor markers, we evaluated cathepsin D assay proficiency by using control samples with intra- and interassay CVs of 2-8% and 10-13%, respectively. Human reference specimens containing known quantities of cathepsin D were developed to facilitate standardized testing. The IRMA procedure and the use of quality-assurance samples permits evaluation of the clinical significance of cathepsin D in human breast cancer trials.
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PMID:Relation between cathepsin D expression and other prognostic factors in breast carcinomas. 758 47

It has been shown that a 90-kDa protein (90K), with an as yet unknown function, is expressed in the majority of human breast-cancer tissues. In addition, the serum level of this 90K antigen is elevated in a certain proportion of breast-cancer patients, and high serum levels are associated with a poor overall survival. It was therefore of interest to determine whether levels of 90K in tumor tissues could be used as a prognostic variable in breast cancer. In the present study, the levels of 90K in primary breast tumor cytosols were studied with respect to the length of relapse-free or overall survival in 547 patients (median follow-up, 81.4 months), and the relationship with response to first-line tamoxifen therapy and the length of progression-free survival in 184 patients with recurrent disease (median follow-up, 59.8 months). 90K levels in tumor cytosols were determined with an immunoradiometric assay. The cytosolic contents of 90K were not significantly correlated with age, menopausal status, tumor size, nodal status or differentiation grade. On the other hand, the levels of 90K were positively correlated with those of cytosolic estrogen receptor, progesterone receptor, urokinase-type plasminogen activator, its inhibitor PAI-I, cathepsin D and PS2. The cytosolic tumor level of 90K was not associated with the rate of relapse or death in primary breast cancer, nor with response to first-line therapy with tamoxifen or the length of progression-free survival in recurrent disease.
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PMID:Expression of tumor-associated 90K-antigen in human breast cancer: no correlation with prognosis and response to first-line therapy with tamoxifen. 761 55

We evaluated levels of mannose-6-phosphate/insulin growth factor-II receptor (M6P/IGFII-R) RNA in 37 breast cancer tumors by quantitative in situ hybridization using a computer-aided image analyzer and compared them to cathepsin D RNA and protein levels in the same tissues. Breast cancer cells expressed more cathepsin D and M6P/IGFII-R RNA than fibroblasts in the same tumors. We found a significant increase of cathepsin D RNA (P = 1 x 10(-5)) and M6P/IGFII-R RNA (P = 0.02) in breast cancer cells compared to epithelial cells of benign mastopathies. There was a positive correlation (r = 0.65; P = 1 x 10(-5)) between M6P/IGFII-R and cathepsin D RNA levels measured on serial sections. This contrasted with the inverse relationship of these 2 RNA species in breast cancer cell lines where estrogen down-regulates M6P/IGFII receptor RNA levels. Moreover, in vivo we found no correlation between the M6P/IGFII-R RNA level and menopausal or estrogen receptor status, suggesting that the in vivo regulation of M6P/IGFII-R RNA differs from its in vitro regulation in cell lines. The M6P/IGFII-R RNA level was not correlated with cathepsin D status, histological grade, and tumor size but was significantly higher in lymph node-positive tumors (P = 0.047). The M6P/IGFII-R could therefore be an additional parameter to predict aggressive breast cancers, complementing cathepsin D assays and other more classical prognostic parameters.
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PMID:Correlation between mannose-6-phosphate/IGFII receptor and cathepsin D RNA levels by in situ hybridization in benign and malignant mammary tumors. 768 51


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