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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 investigated the localization of urokinase-type plasminogen activator (u-PA), type-1 plasminogen-activator inhibitor (PAI-1), u-PA receptor (u-PAR) and alpha(2)-macroglobulin- receptor/low-density-lipoprotein-receptor-related protein (alpha(2)MR/LRP) in human breast tumors by immunohistochemical methods. Frozen sections of 133 primary breast carcinomas, 6 ductal carcinomas in situ and 33 lymph-node metastases were stained with monoclonal antibodies. Formalin-fixed sections of 15 primary tumors and 2 lymph-node metastases were stained with polyclonal antibodies. In primary tumors, u-PA and PAI-1 immunoreactivities were intense in macrophages and mast cells, and moderate in benign and malignant epithelial cells as well as in myofibroblasts and endothelial cells. A sub-group of poorly differentiated tumors showed particularly strong staining of stromal fibroblasts. u-PA immunoreactivity was also present in lymphocytes. alpha(2)MR/LRP and u-PAR immunoreactivities were intense in macrophages, but apart from these cells, alpha(2)MR/LRP was found only in fibroblasts, and u-PAR only in tumor cells located peripherally in tumor-cell clusters and glands and some myofibroblasts in the adjacent stroma. Lymph-node metastases showed staining for u-PA and PAI-1 both of cancer cells and of stromal fibroblasts, also staining for u-PA of lymphocytes. Similarly to some of the poorly differentiated primary tumors, approximately half of the metastases showed very strong staining of stromal fibroblasts, and extracts of these metastases had higher u-PA and PAI-1 levels, as determined by ELISA, than extracts of metastases without this staining pattern. alpha(2)MR/LRP was present only in fibroblasts and u-PAR only in some tumor cells. The presence of u-PA, PAI-1, alpha(2)MR/LRP and u-PAR was controlled biochemically by immunoblotting analyses, ligand-blotting analyses, and direct and reverse zymography. The spatial distribution and the variation in concentration of the various components of the plasminogen-activation system point to a complex, multifunctional role for the 4 proteins in and/or during the development and spread of breast cancer.
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PMID:Immunohistochemical localization of urokinase-type plasminogen activator, type-1 plasminogen-activator inhibitor, urokinase receptor and alpha(2)-macroglobulin receptor in human breast carcinomas. 863 58

The impact of prognostic markers on disease-free and overall survival reflects their relative role in tumour biology. Breast cancer and colon carcinoma can be taken as examples to demonstrate the clinical and biological relevance of 'new markers' of neoplastic disease. In breast cancer, receptor-bound urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 seem to play an important role in the dissolution of the surrounding tissue and the formation of tumour stroma. These processes are prerequisites for invasion and metastasis. The study of 'classical' and 'new' prognostic factors showed that uPA and PAI-1 content of breast cancer tissue are strong and independent prognostic factors. Also in colorectal cancer the prognostic relevance of plasminogen activators and inhibitors was analysed. In particular, low tissue plasminogen activator (tPA) levels, as antigen or as activity, high uPA: tPA antigen ratio in corresponding normal mucosa, high levels of uPA-related antigen and activity and of PAI-2 antigen in neoplastic tissue, and high uPA (neoplastic mucosa): tPA (normal mucosa) ratio, were all parameters associated with a poor overall survival. In conclusion, all these observations show the clinical importance of plasminogen activators and inhibitors at tissue levels with respect to cancer development and survival of patients affected by breast carcinoma or colorectal neoplasia. These new prognostic markers will also permit a better patient selection for a possible adjuvant treatment.
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PMID:Fibrinolysis components as prognostic markers in breast cancer and colorectal carcinoma. 869 36

Cell-surface activation of plasminogen may be important in diseases that involve cellular migration, including atherosclerosis and tumour invasion/metastasis. Cytokeratin 8 (CK 8) has been identified as a plasminogen-binding protein expressed on the external surfaces of hepatocytes and breast carcinoma cells [Hembrough, Vasudevan, Allietta, Glass and Gonias (1995) J. Cell Sci. 108, 1071-1082]. In this investigation, we demonstrate that a soluble form of CK 8 is released into the culture medium of breast cancer cell lines. The released CK 8 is in the form of variably sized polymers that bind plasminogen and promote the activation of [Glu1]plasminogen and [Lys78]plasminogen by single-chain tissue-type plasminogen activator (sct-PA). To assess the mechanism by which CK 8 promotes plasminogen activation, CK 8 was purified from rat hepatocytes and immobilized in microtitre plates. Immobilized CK 8 bound 125I-plasminogen and 125I-sct-PA in a specific and saturable manner. The KDs were 160 +/- 40 nM and 250 +/- 48 nM, respectively. Activation of plasminogen bound to immobilized CK 8 was accelerated compared with plasminogen in solution, as determined using a coupled-substrate fluorescence assay and SDS/PAGE. The ability of CK 8 to promote plasminogen activation may be important in the pericellular spaces surrounding breast cancer cells and at the cell surface.
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PMID:Cytokeratin 8 released by breast carcinoma cells in vitro binds plasminogen and tissue-type plasminogen activator and promotes plasminogen activation. 876 Mar 60

Cytokeratin 8 (CK 8) has been identified on the external surfaces of viable, unpermeabilized epithelial cells (Hembrough, T. A., Vasudevan, J., Allietta, M. M., Glass, W. F., and Gonias, S. L. (1995) J. Cell Sci. 108, 1071-1082). In this study, we demonstrated that CK 8 is the major plasminogen-binding protein in plasma membrane fractions isolated from three breast cancer cell lines, BT20, MCF-7, and MDA-MB-157. To assess the function of CK 8 as a plasminogen receptor, monoclonal antibody 1E8 was raised against the carboxyl-terminal 12 amino acids of CK 8. The 1E8 epitope was present on the external surfaces of breast cancer cells, as determined by immunofluorescence microscopy. 125I-1E8 bound to MCF-7 cells; the maximum binding capacity (1.5 x 10(6) sites per cell) was comparable with that determined for plasminogen. When MCF-7 cells were incubated with Fab fragments of 1E8, specific 125I-plasminogen binding was decreased up to 82%. Specific plasminogen binding was decreased up to 67%, even when the unbound 1E8 Fab was removed by washing the cells prior to adding 125I-plasminogen. Preincubation with 1E8 Fab decreased plasminogen binding to BT20 and MDA-MB-157 cells, although to a lesser extent than with MCF-7 cells. Plasminogen activation by tissue-type plasminogen activator was greatly accelerated, due to a large decrease in Km, when the plasminogen was bound to MCF-7 cells. Pretreatment with 1E8 Fab decreased the rate of plasminogen activation by up to 83%, implicating CK 8 in the MCF-7 cell-accelerated reaction. These studies identify cell-surface CK 8 as a major plasminogen receptor in breast cancer cells and as a required component for the rapid activation of cell-associated plasminogen by tissue-type plasminogen activator.
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PMID:Cell-surface cytokeratin 8 is the major plasminogen receptor on breast cancer cells and is required for the accelerated activation of cell-associated plasminogen by tissue-type plasminogen activator. 881 Mar 46

The conversion of plasminogen to active plasmin is thought to be a crucial step in the process of extracellular matrix degradation associated with metastatic spread. Activation of plasminogen is initiated by urokinase plasminogen activator (uPA). The binding of uPA to the uPA cell surface receptor (uPA-R) accelerates plasmin generation from plasminogen and localizes uPA activity to the cell surface. We investigated the mRNA-expression of uPA-R in 19 different human breast cancer cell lines. In a competitive reverse transcription polymerase chain reaction (cRT-PCR) we simultaneously co-amplified two different RNA templates bearing the same primer recognition sequences, the cell line RNA and a known amount of an in vitro synthesized uPA-R-RNA internal standard. We analyzed the two PCR products differing 50 bp in size by agarose gel electrophoresis and calculated the initial uPA-R-RNA template concentration from the relative intensities of the bands quantified by video densitometry. We grouped the investigated cell lines according to their in vitro invasiveness according to literature. Cell lines with a high potential of invasiveness showed a higher expression of uPA-R compared to those with a low potential of invasiveness (Student's t-test, p 0.04). In addition to that we compared the uPA-R mRNA levels with uPA-R, uPA, and PAI-1 protein levels in culture supernatants and cell lysates. The obtained results in breast cancer cell lines with different invasiveness and in benign epithelial cell lines revealed the complex cooperation of the urokinase type proteolytic pathway. uPA, uPA-R, and PAI-1 are to be considered as a diagnostic tool rather than assaying a particular molecule alone. Our findings support the hypothesis that the urokinase proteolytic pathway plays a central role in the acquisition of an invasive phenotype and favors its potential use as a prognostic marker in patients with breast cancer.
Breast Cancer Res Treat 1996
PMID:Quantification of uPA receptor expression in human breast cancer cell lines by cRT-PCR. 888 68

The relative importance of different proteinases, and their inhibition, in the breakdown of human endothelial basement membrane (BM) by MDA-MB-231 and MCF7ADR human breast cancer cell lines has been studied using 35S-labelled BM-coated 96-well culture plates. Basement membrane degradation (BMD) was independent of cell proliferation above the seeding density. Inhibitors of aspartic (pepstatin and PD 134678-0073) and cysteine proteinases (E64) had little effect on BMD under normal culture conditions, suggesting that cathepsins D, B and L have only a minor role. In contrast, inhibitors of urokinase-type plasminogen activator (uPA) and/or plasminogen activation to plasmin (aprotinin, amiloride, EACA, tranexamic acid, anti-uPA antibody) all reduced BMD by MDA-MB-231 cells by approximately 30-40%, but only in the presence of serum or plasminogen. BB94, an inhibitor of matrix metalloproteinases (MMPs), also reduced BMD by about 30% under these conditions but was similarly effective in serum-free medium. Combinations of BB94 with any of the uPA/plasminogen activation inhibitors in serum-containing medium had additive effects, while BB94 with pepstatin and E64 under serum-free conditions reduced BMD to 16% of control. Serum-containing conditioned medium exhibited appreciable BMD, largely due to aprotinin-inhibitable activity. Although small reductions in cell proliferation were seen with some inhibitors, the combination of BB94 with E64 or E64d reduced the cell population by about 60% under serum-containing conditions. These in vitro observations suggest that combinations of proteinase inhibitors, particularly of uPA/plasminogen activation and MMPs, may merit clinical evaluation as potential antimetastatic therapy for breast cancer.
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PMID:Proteinase inhibitors reduce basement membrane degradation by human breast cancer cell lines. 908 29

Scatter factor (SF) (also known as hepatocyte growth factor) is a plasminogen-related growth factor that induces tumor cell motility, invasion, and angiogenesis. Its receptor is a tyrosine kinase encoded by c-met, a protooncogene. Human breast cancer cells express SF and c-met in vivo; but human breast cancer cell lines do not produce SF in vitro. To determine whether SF can modulate the in vivo growth of human breast cancers within a natural mammary environment, we studied the orthotopic growth of SF-transfected (SF+) versus control (SF-) clones of MDAMB231 human mammary carcinoma cells in the mammary fat pads of athymic nude mice. SF+ clones expressed SF mRNA and produced very high titers of SF protein, whereas SF- clones did not express SF mRNA or produce detectable SF protein. Two SF+ clones (21 and 29) showed significantly increased tumor growth rates, reaching 3- to 4-fold larger primary tumor volumes and weights by time of killing (p < 0.001), as well as higher rates of axillary lymph node metastasis (p < 0.02), as compared with two SF- clones (32 and 34). In contrast, in vitro proliferation rates, two-dimensional colony formation, and soft agar colony formation were no greater in SF+ than in SF- clones. We performed further studies to investigate the discrepancy between the in vivo and in vitro growth results. Tumor extracts from SF+ clone (21 + 29) tumors had 50-fold higher SF content than did SF- clone (32 + 34) tumors, confirming high-level SF expression in vivo in SF+ tumors. Immunostaining of tumor sections for proliferating cell nuclear antigen revealed only a modest increase in the proportion of cycling cells in SF+ versus SF- tumors (70% versus 60%, respectively). The terminal deoxytransferase-labeling index was equally low (approximately 1%) in SF+ and SF- tumors, suggesting that apoptosis was not responsible for the slower growth of SF- tumors. However, SF+ tumors had significantly higher tumor microvessel densities than SF- tumors (p < 0.001). Moreover, there were much higher titers of chemotactic activity for microvascular endothelial cells in cell-conditioned media and primary tumor extracts from SF+ clones as compared with SF- clones. As demonstrated using the rat cornea assay, there was more angiogenic activity in SF+ tumor extracts than in SF- extracts. The increased chemotactic and angiogenic activities in SF+ tumor extracts were not explained by secondary alterations in the content of the angiogenic mediator, vascular endothelial growth factor, or the antiangiogenic glycoprotein, thrombospondin-1; and those activities were neutralized using an anti-SF monoclonal antibody. These findings suggest that SF promotes the orthotopic growth of human breast cancers, at least in part, by stimulating tumor angiogenesis.
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PMID:Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice. 912 Nov 17

During activation of the fibrinolytic system plasminogen is converted to plasmin by tissue plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). t-PA is predominantly released from endothelial cells, u-PA primarily by renal parenchymal cells. The activation of plasminogen is regulated by plasminogen activator inhibitor-1 (PAI-1), plasmin is controlled by alpha 2-plasmin inhibitor. The fibrinolytic system is not only involved in the intravascular dissolution of fibrin (thrombi), it also plays a vital role in normal physiologic reproduction, wound repair, angiogenesis, and tissue remodeling. Fibrinolysis is also a vital component in the pathogenesis of neoplastic disease. It is essential in releasing cells from their primary site of origin, providing nutrition for neoplastic cell growth and promoting cell mobility and motility. In neoplastic cells the degradation of the extracellular matrix proteins is facilitated by excessive expression of u-PA, t-PA, and u-PAR. In many forms of carcinoma increased expression of u-PAR and u-PA is associated with significantly shorter survival. Greater expression of u-PA in breast cancer cells, for example, is associated with shorter survival and increased relapse rate. Progressively aggressive neoplastic cells evidence high expression of u-PA and u-PAR activities, variable expression of t-PA, and enhanced PAI-1 and PAI-2 activities. In acute nonlymphocytic leukemias, poor outcome correlates with high t-PA levels. In acute progranulocytic leukemia there is a high incidence of DIC. Neoplastic prostatic tissue also expresses high u-PA activity and the more aggressive the cell line, the greater the number of u-PAR and the higher the u-PA activity. In gynecologic malignancies, a greater expression of u-PA in combination with cathepsin D is associated with widespread disease and poor prognosis. High u-PA values were also seen in patients with brain, gastric, and hepatic malignancies. It is evident that the plasminogen-plasmin system is a vital component in the biology of neoplastic disease and that it is, in theses conditions, in no way beneficial to the host.
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PMID:The fibrinolytic system in neoplasia. 912 11

Cancer cell invasion is accomplished by the concerted action of several extracellular proteolytic enzyme systems, one of which is the urokinase plasminogen activation system. The different components of this system. e.g. urokinase plasminogen activator (uPA), its receptor uPAR, as well as its main inhibitor plasminogen activator inhibitor type 1 (PAI-1) have all been shown to have prognostic value in breast cancer, i.e. high tumor levels are associated with a poor prognosis. In order to further substantiate the prognostic value of uPA and PAI-1, we have tested the cutpoints (median values and optimized outpoints) from our first study (Cancer Res 53: 2513-2521, 1993) in an independent group of breast cancer patients. Breast cancer cytosols from 100 premenopausal and 150 post-menopausal node positive patients were included. The median observation time was 80 months (range 49-145). Univariate analysis showed that high PAI-1 levels (above the median PAI-1 value) were significantly associated with short recurrence-free survival (RR: 1.65; 95% CI: 1.04-2.63; P = 0.03) and short overall survival (RR: 2.46; 95% CI: 1.52-3.96; P = 0.0001) in postmenopausal patients. Postmenopausal patients with high uPA levels (above the median uPA value) had a significantly shorter recurrence-free survival (RR: 2.04; 95% CI: 1.17-3.56; P = 0.01) and overall survival (RR: 2.07; 95% CI: 1.16-3.70; P = 0.01) than patients with low uPA values. Nearly identical results were obtained when using the optimized PAI-1 or uPA value. In a Cox multivariate analysis which included other established prognostic factors, high PAI-1 was found to be an independent prognostic variable predicting short overall survival with a relative risk of 2.27 in postmenopausal women, and high uPA was found to be an independent prognostic variable predicting short recurrence-free survival with a relative risk of 1.86 in postmenopausal women. The present study indicates that uPA and PAI-1 are independent and significant prognostic variables in subsets of breast cancer patients.
Breast Cancer Res Treat 1997 Apr
PMID:Prognostic significance of PAI-1 and uPA in cytosolic extracts obtained from node-positive breast cancer patients. 913 Dec 71

A long list of potential prognostic markers has been analysed for breast cancer, some of them will be reviewed in this article. The lymph node status is still the best prognostic marker. The lymph node status combined with information on tumour size, receptor- and proliferation status of the tumour should be analysed as standard for all breast cancer patients. Prognostic information for breast cancer patients has also been described for the membrane protein c-erbB2, the protease cathepsin D, plasminogen activators and inhibitors, certain oncogenes and tumour suppressor genes. Some of these factors also give potential additional information on the response to different oncological therapies, and are better denoted predictive factors. In this overview we shortly describe the above mentioned prognostic factors with major focus on the tumour suppressor gene p53 and its prognostic value and potential predictive value.
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PMID:Overview on human breast cancer with focus on prognostic and predictive factors with special attention on the tumour suppressor gene p53. 914 77


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