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)

The serine protease urokinase-type plasminogen activator, uPA, when bound to its specific receptor, uPAR (CD87), plays a significant role in tumor cell invasion and metastasis. In breast cancer, enhanced uPA antigen in the primary tumor is correlated with poor prognosis of the patient. In an in vivo nude mouse model, we tested tumor growth and metastasis of human breast carcinoma cells that had been transfected with an expression plasmid encoding a soluble form of uPAR (suPAR). We explored, whether suPAR/uPA interaction reduces the binding of uPA to cell surface-associated uPAR, and, as a consequence, could suppress tumor growth and metastasis of the human breast cancer cell line MDA-MB-231 BAG. Overexpressed, secreted suPAR was shown to bind and thus scavenge the uPA secreted by the transfected lines suPAR3 and suPAR10. In vitro, an overexpression of suPAR did not alter the proliferation rate of the transfected tumor cells, nor did it affect the expression of uPA. Overexpression of suPAR led to a reduction in the plasminogen activation-related proteolytic activity of breast carcinoma cells. Primary tumor growth in the mammary fat pad of nude mice was followed up for 52 days. Overexpression of suPAR correlated with a reduction in tumor growth (from day 21, reaching 30% by day 34) as well as lung colonization (lung metastasis-positive mice in suPAR3: 4 of 17; suPAR10: 3 of 10; parental MDA-MB-231 BAG: 13 of 18). We conclude that suPAR overexpression leading to effective scavenge of uPA impairs proteolysis as well as the tumor growth and metastatic potential of breast carcinoma cells in vivo.
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PMID:Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the soluble urokinase-type plasminogen activator receptor (CD87). 1077 Jun 39

Selective estrogen receptor modulators, like tamoxifen and related compounds, have mixed estrogen agonistic/antagonistic effects. Tamoxifen may confer significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Droloxifene, a structural analogue of tamoxifen, has estrogen agonistic effects on bone and antagonistic effects on endometrial and breast tissue. Its cardiovascular effects in women are unknown. We enrolled 24 healthy postmenopausal women in a randomized, double-blind, 2-period crossover trial comparing the effects of droloxifene (60 mg/d) with conjugated estrogen (0.625 mg/d). Plasma lipids, coagulation and fibrinolytic factors, and brachial flow-mediated vasodilator responses were measured at the beginning and end of each treatment period. Droloxifene and estrogen resulted in 16.6% and 12.0% reductions, respectively, in low density lipoprotein cholesterol (P<0.001) and 13.2% and 9.5% reductions, respectively, in lipoprotein(a) (P<0.05). In contrast, estrogen, but not droloxifene, increased high density lipoprotein (18.5%, P<0.001). Droloxifene also reduced fibrinogen by 17.8% versus a 7.3% reduction with estrogen (P=0.004) but produced no estrogen-like changes in plasminogen, plasminogen activator inhibitor-1, or tissue plasminogen activator. Droloxifene and estrogen produced 36.4% and 27.3% increases, respectively, in flow-mediated vasodilation (percent change from baseline, P<0.05 for both). Droloxifene has estrogen agonistic properties regarding low density lipoprotein and lipoprotein(a) metabolism, certain coagulation factors, and endothelium-dependent vasodilation but, unlike estrogen, has no effect on high density lipoprotein/triglyceride metabolism and the fibrinolytic cascade. It remains unknown whether droloxifene can confer a true cardiovascular benefit.
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PMID:Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women. 1084 79

We have previously shown that platelet-produced thrombospondin-1 up-regulates the urokinase plasminogen activator and its receptor and promotes tumour cell invasion. Although tumour cells produce thrombospondin-1 in vivo, they produce only minimal amounts of thrombospondin-1 in vitro. To determine the effect of tumour cell-produced thrombospondin-1 in the regulation of the plasminogen/plasmin system and tumour cell invasion, we studied THBS-1-transfected MDA-MB-435 breast cancer cells that overexpress thrombospondin-1. The role of urokinase plasminogen receptor in thrombospondin-1-mediated adhesion and invasion was studied by antisense inhibition, enzymatic cleavage and antibody neutralization. Tumour cell adhesion to collagen and laminin was evaluated. Tumour cell invasion was studied in a modified Boyden chamber collagen invasion assay. Tumour cell thrombospondin-1 induced a 2-7 fold increase in urokinase plasminogen activator receptor and cell-associated urokinase plasminogen activator expression and a 50-65% increase in cell-associated urokinase plasminogen activator and plasmin activities. Furthermore, tumour cell thrombospondin-1 promoted tumour cell invasion and decreased tumour cell adhesion through up-regulation of urokinase plasminogen activator receptor-controlled urokinase plasminogen activator and plasmin activities. We conclude that tumour cell-produced thrombospondin-1 may play a critical role in the regulation of tumour cell adhesion and tumour cell invasion.
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PMID:Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor. 1091 42

Breast cancer cells (BCC) frequently metastasize to bone where they may cause tumor-induced osteolysis (TIO). While the important eroding role of the osteoclasts in TIO is well admitted, the possibility that BCC and/or osteoblasts activated by tumoral factors could also directly degrade bone matrix in this pathology has been much less investigated. We show here that the net collagen amount produced in vitro by normal human osteoblasts and osteoblast-like cells was significantly reduced by culture medium conditioned by several BCC lines, including three newly isolated ones. There was no evidence for a decrease in collagen synthesis, as assessed by the production of the carboxyterminal propeptide of type I collagen. In contrast, the effect of BCC-derived medium on collagen amount was attenuated by inhibitors of matrix metalloproteinases (MMPs) as well as by tranexamic acid, an inhibitor of the plasminogen conversion to plasmin, while it was abolished in presence of the two kinds of proteinase inhibitors. This osteoblastic protein degradation activity appeared to be attributable to factors secreted by the osteoblasts as well as by BCC. These factors had molecular weights lower as well as higher than 10 kD. Our data suggest that besides the eroding action of osteoclasts, BCC- and osteoblast-derived MMPs and serine proteinases might play a direct role in bone collagen degradation in TIO.
Breast Cancer Res Treat 2000 May
PMID:Protein production by osteoblasts: modulation by breast cancer cell-derived factors. 1093 90

Cancer invasion is induced by several proteolytic enzyme systems associated with the destruction of basement membrane and extracellular matrix. Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have been reported as prognostic factors in breast cancer patients and plasminogen activation is regulated by various factors such as uPAR and growth factors. Thus, we examined the tissue levels of urokinase-type plasminogen activator receptor (uPAR) in breast cancer patients. Tissue uPAR levels were measured by ELISA assay in 268 breast cancer patients. The median and mean values of tissue uPAR level in breast cancer were 3.5 ng/mg cytosol protein and 4.8+/-3.6 ng/mg cytosol protein, respectively. Tissue uPAR level was the highest in T1 stage, but there was no statistical significance between the T stages (p>0.05), nor in nodal stage, in the value of uPAR according to progression. And the value of uPAR expression was not associated with estrogen and progesterone receptor status, number of involved node and percent of node involvement. In TNM stage, tissue uPAR levels were higher in patients with stage I-II than in patients with stage III-IV (p=0.027). In univariate analysis, nodal factor (p=0.002) and TNM stage (p=0.0004) were significant. But, multivariate analysis showed that TNM stage was the only significant prognostic factor (p=0.0002). These results suggest that uPAR is mainly associated with initial tumor invasion and other factors might be involved in later stages of cancer progression.
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PMID:Tissue urokinase-type plasminogen activator receptor levels in breast cancer. 1093 93

Matriptase is an epithelial-derived, integral membrane serine protease. The enzyme was initially isolated from human breast cancer cells and has been implicated in breast cancer invasion and metastasis. In the current study, using active matriptase isolated from human milk, we demonstrate that matriptase is able to cleave various synthetic substrates with arginine or lysine as their P1 sites and prefers small side chain amino acids, such as Ala and Gly, at P2 sites. For the most reactive substrates, N-tert-butoxycarbonyl (N-t-Boc)-gamma-benzyl-Glu-Ala-Arg-7-amino-4-methylcoumarin (AMC) and N-t-Boc-Gln-Ala-Arg-AMC, the K(m) values were determined to be 3. 81 and 4.89 microm, respectively. We further demonstrated that matriptase can convert hepatocyte growth factor/scattering factor to its active form, which can induce scatter of Madin-Darby canine kidney epithelial cells and can activate c-Met tyrosine phosphorylation in A549 human lung carcinoma cells. In addition, we noted that matriptase can activate urokinase plasminogen activator but has no affect on plasminogen. These results suggest that matriptase could act as an epithelial, upstream membrane activator to recruit and activate stromal-derived downstream effectors important for extracellular matrix degradation and epithelial migration, two major events of tissue remodeling, cancer invasion, and metastasis.
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PMID:Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. 1096 9

The urokinase-dependent activation of plasminogen by breast cancer cells plays an important role in metastasis. We have previously shown that the metastatic breast cancer cell line MDA-MB-231 over-expresses urokinase and binds and efficiently activates plasminogen at the cell surface compared to non-metastatic cells. The aim of this study was to further characterise plasminogen binding and determine the topology of cell surface-bound plasminogen in terms of its potential for activation. The lysine-dependent binding of plasminogen at 4 degrees C to MDA-MB-231 cells was stable and resulted in an activation-susceptible conformation of plasminogen. Topologically, a fraction of bound plasminogen was co-localised with urokinase on the surfaces of MDA-MB-231 cells where it could be activated to plasmin. At 37 degrees C plasmin was rapidly lost from the cell surface. Apart from actin, other candidate plasminogen receptors were either not expressed or did not co-localise with plasminogen at the cell surface. Thus, based on co-localisation with urokinase, plasminogen binding is partitioned into two functional pools on the surface of MDA-MB-231 cells. In conclusion, these results shed further light on the functional organisation of the plasminogen activation cascade on the surface of a metastatic cancer cell.
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PMID:The topology of plasminogen binding and activation on the surface of human breast cancer cells. 1155 45

The paper presents recent data on the role of oncogenes and suppressive genes, receptors of steroidal hormones, secretory protein pS2, cathepsin D, urokinase and tissue plasminogen activators and their inhibitor PAI-I, polypeptide growth factors and somatostatin and their receptors in the evaluation of proliferative activity and drug therapy responses and in the prediction of disease and on the simultaneous estimation of the limited number of mutually complementing parameters that can characterize the proliferative activity of a tumor, its metastatic potential and sensitivity to different types of overall and regional regulation. The main task for investigators engaged in this area is to choose a qualitatively and quantitatively optimal ratio of molecular markers of breast cancer to evaluate the biological behavior of a tumor.
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PMID:[Modern prospects for molecular-biochemical methods for evaluating biological "behavior" of breast neoplasms]. 1167 60

Cytokeratin 8 (K8) is a member of the intermediate filament (IF) gene family expressed by simple epithelial cells and by some carcinoma cells. The majority of the cellular K8 is assembled with its partner, K18, into highly insoluble 10 nm filaments that extend from the nucleus to the internal leaflet of the plasma membrane. At desmosomes and hemidesmosomes, K8, K18, and other IF proteins are bridged to proteins with transmembrane domains by a family of proteins called plakins. K8 does not have a signal peptide or a well-defined transmembrane domain; however, there is substantial evidence that this protein is available to bind plasminogen and K8-specific antibodies on the surfaces of certain epithelial cells in culture, including hepatocytes, hepatocellular carcinoma cells, and various breast cancer cell lines. This may reflect a novel mechanism of protein penetration through the plasma membrane or binding of secreted K8 to other cell-surface molecules. Cancer cells are known to secrete K8-containing protein complexes in vitro and in vivo. These complexes bind plasminogen as well. The plasminogen-binding activity of K8 is unique amongst IF proteins, probably because its sequence includes a carboxyl-terminal Lys residue. However, a K8 mutant that lacks the C-terminal Lys still binds plasminogen, albeit with decreased affinity. K18 does not bind plasminogen; however, K8 and K18 bind tissue-type plasminogen activator (tPA) equivalently. tPA-binding to K18 may be important in the mechanism whereby K8-K18 complexes promote plasminogen activation by tPA. Numerous studies have demonstrated correlations between high levels of K8 expression and increased migration and invasion of certain cancer cells. These correlations are most easily explained by the function of IF proteins in determining the rigidity of the cytoskeleton; however, the function of cell-surface K8 as a plasminogen receptor merits consideration. We have demonstrated that certain aggressive breast cancer cell lines, which have highly activated endogenous urokinase type-plasminogen activator (uPA)-uPA receptor (uPAR) systems, do not express high levels of cell-surface K8. The membrane macromolecule that is responsible for plasminogen-binding and for supporting activation of plasminogen by uPA on the surfaces of these cell types remains to be determined. This review focuses on the function of K8 as a plasminogen receptor and its potential role in cancer.
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PMID:Cytokeratin 8 functions as a major plasminogen receptor in select epithelial and carcinoma cells. 1168 50

Functional significance of several oncogenes is mediated by overexpression. To identify overexpressed genes in prostate cancer, we analyzed expression of 1081 transcripts in three prostate cancer cell lines (PC-3, DU145, and LNCaP) using cDNA microarray hybridization. The cDNA microarray analyses were validated by quantitative real-time RT-PCR. On average, 64% of the genes were expressed at detectable levels in the cell lines. Next, the expression profiles were combined with the data on DNA sequence copy number alterations in the cell lines obtained by comparative genomic hybridization. The genes for Elongin C and urokinase type plasminogen-activator, both located in the regions of amplification in the PC-3 cell line (8q21 and 10q22, respectively), were found to be overexpressed in the PC-3. Amplification and overexpression of urokinase type plasminogen-activator in prostate cancer has previously been reported. Here, fluorescence in situ hybridization on tissue microarray showed high-level amplification of the Elongin C gene in 8 (23%) of 35 hormone-refractory carcinomas but in none of the untreated prostate carcinomas (n = 35). Finally, it was shown that the Elongin C gene was overexpressed and amplified also in breast cancer cell line SK-Br-3. The results indicate that Elongin C is a putative target gene for 8q amplification.
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PMID:Amplification and overexpression of Elongin C gene discovered in prostate cancer by cDNA microarrays. 1200 3


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