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

A number of growth factors have been implicated in the control of the proliferation of breast cancer cells and some have been reported to mediate the proliferative effects of oestradiol. MCF-7 cells were treated with growth factors in the presence and absence of oestradiol. Oestradiol increased the response of cells to the proliferative effects of epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha) and basic fibroblast growth factor (bFGF). Platelet derived growth factor (PDGF) and cathepsin D had no effect in the presence or absence of oestradiol while TGF-beta slightly reduced the stimulation by oestradiol. In the absence of oestradiol, there was little effect of combinations of growth factors although the effects of bFGF and IGF-I were additive. In the presence of oestradiol, the effects of bFGF and TGF-alpha were additive whereas bFGF acted as an IGF-I antagonist. Overall, bFGF had the greatest effect on cell proliferation although this was less marked than the previously described effect of the IGFs and insulin. The effects of oestradiol on the sensitivity of cells to the proliferative effects of bFGF did not appear to result from regulation of bFGF receptor expression.
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PMID:Modulation of the proliferative response of breast cancer cells to growth factors by oestrogen. 141

In this study, the polyanionic compound suramin was shown to be a potent in vitro growth inhibitor of both hormone-insensitive, estrogen receptor-negative human breast cancer cells (MDA MB231 and SK-BR-3) and hormone-responsive, estrogen receptor-positive human breast cancer cells (ZR 75-1, T47D, and MCF7). The inhibitory effect of suramin was dose dependent, with a median effective dose varying from 7 microM for MDA MB231 cells to 50 microM for MCF7 cells. This result indicated that estrogen receptor-negative cells were more sensitive to the drug. In MCF7 cells, not only did suramin block the mitogenic action of growth factors such as epidermal growth factor (EGF) and insulin-like growth factors I and II (IGF-I and IGF-II, respectively), but it also totally abolished the increase in cell proliferation induced by the steroid hormone 17 beta-estradiol (E2). Maximal inhibition was obtained after 5 days of suramin treatment, and inhibition either was partially reversed by E2, IGF-I, and IGF-II or was not reversible by EGF following removal of drug. In addition, suramin significantly decreased synthesis and secretion of the lysosomal enzyme cathepsin D, which was shown to be associated with a high risk of breast tumor metastasis. These results therefore suggest that, because of its effects on growth and cathepsin D secretion, suramin might be a helpful additional therapeutic tool for breast cancer patients, especially for patients with estrogen receptor-negative tumors which are insensitive to antihormonal strategies.
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PMID:Inhibition of breast cancer growth by suramin. 173 71

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

The precursor of cathepsin D, a lysosomal acidic protease, is secreted by human breast cancer cells, where its synthesis is specifically induced by estrogens and growth factors. In this study, we investigated the hormonal regulation of cathepsin D and its mRNA in uterine cells. In the Ishikawa endometrial cancer cell line, epidermal growth factor (EGF) increased the level of cathepsin D and its mRNA 2- to 3-fold. Although expression of the transiently transfected estrogen-responsive recombinant (Vit. tk. CAT) and the endogenous progesterone receptor was markedly increased by estradiol in Ishikawa cells, estradiol did not alter the level of cathepsin D or its mRNA. The progestin R5020 induced the expression of the LTR sp65 CAT, which contains the progesterone-responsive element of the MMTV but it too was without effect on cathepsin D. By contrast, the expression of cathepsin D gene, in normal rat uterus, was increased by R5020 but not by estradiol. We conclude that cathepsin D gene expression is regulated differently by sex steroid hormones in endometrial and breast cancer cell lines, whereas it is similarly induced by EGF in these cells.
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PMID:Differential regulation of cathepsin D by sex steroids in mammary cancer and uterine cells. 261 33

The estrogen-induced 52K protein secreted by human breast cancer cells is a lysosomal protease recently identified as a pro-cathepsin D by sequencing several cDNA clones isolated from MCF7 cells (Augereau et al., Mol. Endocr.). Using one of these clones, we detected, in MCF7 cells, a 2.2 kb mRNA whose level was rapidly increased 4- to 10-fold by estradiol, but not by other classes of steroids. Other mitogens, such as epidermal growth factor and insulin, also induced the 2.2 kb mRNA in a dose-dependent manner. Induction with epidermal growth factor was as rapid but was 2- to 3-fold lower than with estradiol. Antiestrogens had no effect on the 52K-cathepsin-D mRNA in MCF7 cells, but became estrogen agonists in two antiestrogen-resistant sublines R27 and LY2. The use of transcription and translation inhibitors and nuclear run-on experiments indicate that estradiol enhances transcription of the 52K-cathepsin-D gene in MCF7 cells.
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PMID:Estrogens and growth factors induce the mRNA of the 52K-pro-cathepsin-D secreted by breast cancer cells. 328 24

Mutation and overexpression of p53 occurs in 20-40% of breast cancers and has been shown to be an independent prognostic indicator. Recently we have demonstrated prostate-specific antigen (PSA) expression in breast tumours to be suggestive of favourable prognosis, but quantitative relationships between PSA and p53, and between these and other prognostic factors in breast cancer, have not been investigated. Time-resolved immunofluorometric procedures were used to quantify both p53 protein and PSA in 200 breast tumour extracts, which were also assayed for oestrogen (ER) and progesterone receptors (PGR), epidermal growth factor receptors (EGFR), cathepsin D and HER-2/neu, and characterised for S-phase fraction and DNA ploidy. Weak Spearman correlations were found between p53 and ER (r = - 0.18, P = 0.010), PGR (r = - 0.15, P = 0.0385) and S-phase fraction (r = 0.17, P = 0.016), while PSA was correlated only with PGR (r = 0.16, P = 0.025). Wilcoxon rank sum analysis revealed that levels of ER (P = 0.0001), PGR (P = 0.0001), S-phase fraction (P = 0.0001) and EGFR (P = 0.0014) differed significantly between the two groups categorised as p53 negative or p53 positive. Tumours classified as PSA negative or PSA positive were found to differ with respect to PGR (P = 0.0091) and S-phase fraction (P = 0.011) in a similar analysis. Contingency tables indicated significant negative associations between the status of p53 and that of ER (P = 0.003) and PGR (P = 0.001) and between PSA and S-phase fraction (P = 0.012), and positive associations between p53 and EGFR (P = 0.017), HER-2/neu (P = 0.008), S-phase fraction (P = 0.001) and aneuploidy (P = 0.007), and between PSA and both ER (P = 0.061) and PGR (P = 0.010). No significant associations were found between p53 and PSA. Our results demonstrate that the presence of p53 in breast tumours relates to several other variables which are suspected to predict aggressive tumour phenotypes and that the presence of PSA relates to variables associated with good prognosis.
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PMID:Immunofluorometric analysis of p53 protein and prostate-specific antigen in breast tumours and their association with other prognostic indicators. 754 16

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

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds elicit diverse toxic and biochemical responses in laboratory animals and mammalian cells in culture. TCDD induces CYP1A1 gene expression and results of extensive research have delineated the molecular mechanism of this response. In target cells, TCDD initially binds to the aryl hydrocarbon (Ah) receptor which accumulates in the nucleus as an Ah-receptor:aryl hydrocarbon nuclear translocator (Arnt) protein heterodimeric complex. The nuclear Ah receptor complex acts as a ligand-induced transcription factor which binds to transacting genomic dioxin/xenobiotic responsive elements (DREs/XREs) located in the 5'-regulatory region upstream from the initiation start site and this interaction results in transactivation of gene transcription. DREs have been identified in several other genes which are induced by TCDD, including CYP1A2, aldehyde-3-dehydrogenase, NAD(P)H quinone oxidoreductase, and glutathione S transferase Ya and similar induction response pathways have been observed or proposed. However, TCDD and other Ah receptor agonists also inhibit expression of several genes and research in this laboratory has investigated inhibition of estrogen (E2)-induced genes including uterine epidermal growth factor, c-fos protooncogene, and the progesterone receptor, estrogen receptor (ER) and cathepsin D genes in human breast cancer cell lines. In MCF-7 human breast cancer cells, E2 induces cathepsin D gene expression and this is associated with formation of an ER/Sp1 complex at the sequence in the promoter region (-199/-165) of this gene. Within 30 min TCDD causes a rapid inhibition of E2-induced cathepsin D gene expression in MCF-7 cells. Moreover, using a series of synthetic oligonucleotides which include the wild-type ER/Sp1 and various mutants, it was shown by gel electromobility shift and transient transfection assays that the nuclear Ah receptor complex binds to an imperfect DRE located between the ER and Sp1 binding sequences. This interaction results in disruption of the ER/Sp1 complex and inhibition of E2-induced gene expression. These results illustrate that the nuclear Ah receptor complex also exhibits activity as a negative transcription factor via a mechanism which is similar to that reported for Ah receptor-mediated induction of gene expression.
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PMID:Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression. 778 96

Epithelial cells in situ can internalize their desmosomes. This can be induced in cell cultures after removal of calcium ions from the cell medium. To study this endocytic process, a nontumorigenic human breast epithelial cell line, HMT-3522, was used. HMT-3522 cells were grown in serum-free, chemically defined medium, containing epidermal growth factor (EGF). Removal of EGF from the medium led to growth arrest and a kind of epithelial differentiation process in which adjacent cells interdigitated and formed more desmosomes than in the proliferating state. Growth-inhibited HMT-3522 cells dissociated following EGTA treatment, the desmosomes divided in a symmetrical fashion, and the desmosomal plaques (half-desmosomes) on the cell surface became internalized. The internalization was independent of clathrin, since immunogold labeling of ultracryosections never showed clathrin on desmosomal plaque-associated membrane domains. Moreover, cytosol acidification, which selectively inhibits endocytosis from clathrin-coated pits, practically blocked the uptake of transferrin, whereas internalization of desmosomal plaques continued. In contrast, actin filaments appeared to be involved in the desmosomal internalization. Thus, depolymerization of actin filaments by cytochalasin D significantly reduced endocytosis of half-desmosomes. Immunogold labeling showed that the vesicles with desmosomal plaques were not enriched in MPR (cation-independent mannose-6-phosphate receptor), cathepsin D or the lysosome-associated membrane protein lamp-1. In addition, the morphology was different. Thus, the endocytic vesicles with desmosomal plaques represent a special compartment, distinct from typical endosomes and lysosomes.
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PMID:Endocytosis of desmosomal plaques depends on intact actin filaments and leads to a nondegradative compartment. 792 92

In the natural history of post-menopausal patients with primary breast cancer, high estrogen receptor levels (ER) have been associated with a poor recurrence-free survival. The purpose of this study was to investigate whether there are any biological intratumoral characteristics to support this puzzling clinical observation. In a population of 542 post-menopausal, primary-breast-cancer patients, 3 normal distributions fitted into the frequency distribution curve of the logarithmically transformed ER-EIA values. The biological profiles of the low ER group, and of the intermediate and high ER groups identified in the ER-positive population were compared. Parameters correlated with ER functional aspect (progesterone receptors and PS2), receptors of epidermal growth factor (EGFR), protease cathepsin D and tumor proliferation (deduced from thymidine kinase activity) were analyzed. As previously reported, the levels of progesterone receptors and PS2 increased significantly from the low to the high ER groups. The highest levels of cathepsin D and thymidine kinase which have been previously related to a poor prognosis in breast cancer were found in the low ER group, but high levels were, surprisingly, also found in the high ER group. This study indicates that the ER-positive post-menopausal population is biologically heterogeneous. The high levels of thymidine kinase found in the high ER group suggest that overexpression of ER may be associated with proliferation enhancement, partly explaining the poor spontaneous prognosis related to this subset.
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PMID:Biological heterogeneity of ER-positive breast cancers in the post-menopausal population. 792 97


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