Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have measured the activity of the cysteine proteinase cathepsin B, the inhibitory activity of cysteine proteinase inhibitors and the amounts of cathepsins B, H and L in normal sera and sera from patients with breast cancer, as well as in tissue homogenates of tumorous and non-tumorous samples. The amounts of cathepsin B, determined by ELISA in tumour sera (n = 17) were significantly higher than the amounts determined in normal sera (n = 20). On the other hand, the differences in the amounts measured in tumour sera were not significant when compared with the known histopathological characteristics. In cytosols of breast cancer tumour tissue in general, the level of cathepsin H was higher than those of cathepsins B and L in all samples tested. In the same samples, at least a 10-fold increase of cathepsin B (activity and quantity) was detected in matched pairs (n = 20) of carcinoma and normal tissue of the same breast (p less than 0.01). The amount of cathepsin B correlated with the degree of malignancy inside the histological subtypes of invasive ductal carcinoma (n = 90, p less than 0.01). In addition, a negative correlation of values for cathepsin B with the involvement of regional lymph nodes (n = 75, p less than 0.01) was found inside the same group. In contrast, the activities of cysteine proteinase inhibitors did not correlate with any of the known clinical data. Our data provide further indirect evidence for the involvement of cathepsin B in the processes of tumour growth and metastasis in breast carcinoma. The follow-up studies will verify the prognostic value of these findings.
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PMID:Cathepsins B, H and L in human breast carcinoma. 131 76

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. Receptor-bound urokinase-type plasminogen activator (uPA) appears to play a key role in these events. uPA converts plasminogen into plasmin and thus mediates pericellular proteolysis during cell migration and tissue remodeling under physiological and pathophysiological conditions. uPA is secreted as an enzymatically inactive proenzyme (pro-uPA) by tumor cells and stroma cells. uPA exerts its proteolytic function on normal cells and tumor cells as an ectoenzyme after having bound to a high-affinity cell surface receptor. After binding, pro-uPA is activated by serine proteases (e.g. plasmin, trypsin or plasma kallikrein) and by the cysteine proteases cathepsin B or L, resp. Receptor-bound enzymatically active uPA converts plasminogen to plasmin which is bound to a different low-affinity receptor on tumor cells. Plasmin then degrades components of the tumor stroma (e.g. fibrin, fibronectin, proteoglycans, laminin) and may activate procollagenase type IV which degrades collagen type IV, a major part of the basement membrane. Hence receptor-bound uPA will promote plasminogen activation and thus the dissolution of the tumor matrix and the basement membrane which is a prerequisite for invasion and metastasis. Tissues of primary cancer and/or metastases of the breast, ovary, prostate, cervix uteri, bladder, lung and of the gastrointestinal tract contain elevated levels of uPA compared to benign tissues. In breast cancer uPA and PAI-1 antigen in tumor tissue extracts are independent prognostic factors for relapse-free and overall survival.
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PMID:Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. 151 91

In order to evaluate the role of cathepsin B (CB) as a proteinase involved in mammary tumor progression and its potential role as a tumor marker, we have measured the CB activity in cytosols of breast cancer tumor tissue using Z-Arg-Arg-AMC as the substrate and found a 23fold increase when compared to distantly located breast tissue from the same patient. In addition, urine of breast cancer patients under adjuvant chemotherapy was screened for CB immunoreactivity with a sandwich type enzyme immunoassay which revealed significant interindividual differences in concentrations with some urines containing immunoreactivity comparable to healthy controls. The urines were also investigated for CB activity but no differences between patients and controls were observed. However, urine contains thiol activatable proteinases causing substrate hydrolysis, which is to a varying extent inhibited by E-64 or Z-Phe-Phe-CHN2.
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PMID:Detection of cathepsin B in tumor cytosol and urine of breast cancer patients. 180 22

Tumor cell invasion and metastasis is a multifactorial process, which at each step may require the action of proteolytic enzymes such as collagenases, cathepsins, plasmin, or plasminogen activators. An enzymatically inactive proenzyme form of the urokinase-type plasminogen activator (pro-uPA) is secreted by tumor cells which may be converted to an enzymatically active two-chain uPA-molecule (HMW-uPA) by plasmin-like enzymes. Action of proteases on pro-uPA may generate the enzymatically active or inactive high-molecular-weight form of uPA (HMW-uPA). Some proteases (plasmin, cathepsin B and L, kallikrein, trypsin or thermolysin) activate pro-uPA by cleaving the peptide bond Lys158 and IIe159. Other proteases (elastase, thrombin) cleave pro-uPA at different positions to yield enzymatically inactive HMW-uPA. HMW-uPA may be split into the enzymatically active LMW-uPA and the enzymatically inactive ATF (amino terminal fragment). ATF may be cleaved between peptide sequence 20 and 40 within the receptor binding domain of uPA (GFD). Such impaired ATF does not bind to uPA-receptors. Action of the bacterial endoproteinase Asp-N from Pseudomonas fragi mutant on pro-uPA or HMW-uPA, however, generates intact ATF which efficiently competes for binding of HMW-uPA or pro-uPA to receptors on tumor cells. High uPA-antigen content (pro-uPA, HMW-uPA, or LMW-uPA) in breast cancer tissue (not in plasma) indicates an elevated risk for the patient of recurrences and shorter overall survival. Thus pro-uPA/uPA-antigen content in breast cancer tissue serves as an independent prognostic parameter for the outcome of the disease. Cathepsin D is also an independent prognostic factor for recurrences and overall survival. High content of cathepsin D in breast cancer tumors is, however, not correlated with elevated levels of pro-uPA/uPA indicating that synthesis and release of cathepsin D and pro-uPA/uPA are independent events.
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PMID:Biological and clinical relevance of the urokinase-type plasminogen activator (uPA) in breast cancer. 180 51

A precursor form of cathepsin B (Mr 45-47 kd) was purified from ascitic fluids of patients with ovarian adenocarcinomas. Following pepsin activation, this precursor produced a 33 kd cathepsin B-like proteinase closely related to lysosomal cathepsin B. A similar activation was found using the 52 kd pro-cathepsin D secreted by the MCF7 human breast cancer cells. This activation was a time, dose and pH dependent process. These results suggest that the 52 kd pro-cathepsin D may be involved in the early steps of the "metastatic cascade", activating pro-cathepsin B in an acidic environment.
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PMID:[Pro-cathepsin D can activate in vitro pro-cathepsin B secreted by ovarian cancers]. 250 Feb 29

The cysteine proteinase cathepsin B (EC 3.4.22.1) has been proposed to play an important role in the proteolytic mechanism of the ability of breast cancer cells to invade into and through normal tissues during metastasis. In this study, activity of cathepsin B was measured with a fluorometric microtiter plate assay in human breast tumors as well as in mammary gland dysplasias and in four human breast cancer cell lines (BT-20, MDA-MB-231, PMC42 and T47D). 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. All investigated breast cancer cell lines display positive cytochemical staining for cathepsin B activity with granular pattern of distribution of the final reaction product. Biochemically, the breast cancer cell lines differed significantly from each other in the level of cathepsin B activity decreasing in the following order: T47D, PMC42, MDA-MB-231 and BT-20.
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PMID:Cathepsin B in human breast tumor tissue and cancer cells. 270 24

The inhibitory profiles of several proteinase-like peptidases active on synthetic peptide (MCA) substrates, present in sera and 100,000g supernatants of malignant tissue from patients with breast cancer, have been studied using a series of known inhibitors including epoxysuccinyl peptides (E-64, Ep-475), Z-Phe-Phe-diazomethane, PMSF, iodoacetamide, 1-10-O-phenanthroline, leupeptin, aprotinin, elastatinal and alpha 2-macroglobulin. While in general the inhibition profiles confirmed reported substrate specificities some anomalies were observed. In particular, the serum activities on two cathepsin B substrates were unaffected by specific cysteine proteinase inhibitors and in breast tissue only 20-37% of activity towards these two substrates was apparently due to the presence of endopeptidases. However, the potent inhibition of other proteinase-like activities by the epoxysuccinyl peptides and leupeptin, or similar inhibitors, may be useful agents in the study of methods of combating tumour spread.
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PMID:Inhibition of proteinase-like peptidase activities in serum and tissue from breast cancer patients. 305 53

A latent cysteine proteinase has been found in the pleural effusion fluid of patients with breast cancer. It can be converted by pepsin to an active form, the properties of which, including the pH optimum, pH stability, substrate specificity, and sensitivity to various proteinase inhibitors, were found to be closely related to those of cathepsin B. Unlike the pepsin-generated enzyme, which was rapidly inactivated above pH 7.0, the latent enzyme showed substantially higher stability in the region around and above neutral pH. The apparent Mr values of the latent and pepsin-generated enzyme forms were approximately 45,000 and 32,000, respectively. Both enzyme forms exhibited heterogeneous binding affinity to concanavalin A-Sepharose 4B. Altogether, our results demonstrate that a latent cathepsin B form occurs in vivo in pleural effusions of breast cancer patients.
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PMID:A latent form of cathepsin B in pleural effusions. I. Characterization of the enzyme in breast cancer patients. 311 8

The proteolytic activity of serum against two synthetic polypeptide substrates conjugated with 7-amino-4-methylcoumarine which are known to be highly specific substrates for lysosomal cathepsin B-like cysteine proteinase, was studied in normal individuals and in patients with breast and colorectal cancer. The results showed that both substrates are cleaved in different ways and their hydrolysis is very poorly sensitive to inhibitors of cysteine proteinases. On the other hand, cleavage is intensively inhibited by disodium-EDTA which is known as an activator of cysteine proteinases. This indicates that lysosomal conditions are quite different from serum which is an unstable mixture of various enzymes and their substrates. It was also demonstrated that hydrolysis of the tested substrates is not probably realized by cysteine proteinases but it can be performed by cooperation of other serum proteinases. Moreover, our results confirmed that serum activity of these enzymes can be significantly higher in patients with breast cancer, particularly with metastasis, than in healthy women. A slight insignificant increase was observed also in patients with colorectal cancer.
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PMID:Clinical experience with the testing of serum proteinase activity by cathepsin B-like sensitive amino acid derivatives of 7-amino-4-methylcoumarine. 312 64

Human breast cancer cell lines, as well as transformed mammary epithelial cells (HBL-100) and growth-stimulated normal breast epithelial cells showed positive cytochemical reaction with the proteinase substrate 2-(N-benzyloxycarbonyl-L-arginyl-L-arginylamido)-4-methoxynapht halene, in the presence of 5-nitrosalicylaldehyde. The reaction product, small fluorescent granules, was distributed throughout the cytoplasm, in the perinuclear zone, in some cytoplasmic projections, and at the cell surface. Using a panel of various proteinase inhibitors, we found that the formation of the reaction product was an enzymic function of a cysteine proteinase. Using the substrate 7-(N-benzyloxycarbonyl-L-arginyl-L-arginylamido)-4-methylcoumarin, we evaluated some biochemical properties of the cysteine proteinase, including pH-activity profile, pH stability, apparent relative molecular mass and sensitivity toward various proteinase inhibitors. We found that the proteinase from the studied breast epithelial cells exhibited characteristics of a mature form of cathepsin B. Taken together, the cytochemical and biochemical data provide evidence that human breast epithelial cells of cancer origin, as well as in the transformed or growth-stimulated state express active cathepsin B and compartmentalize it into specific subcellular sites.
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PMID:Cytochemical and biochemical evidence of cathepsin B in malignant, transformed and normal breast epithelial cells. 366 10


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