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 purpose of this retrospective multicentre study was to assess the prognostic value of urokinase plasminogen activator (uPA) and p53 levels in a large series of primary breast cancer, using an automatic quantitative luminometric method. Samples of 1245 operable breast tumours were collected from seven French institutions and patients were followed for a median of 75 months. The median uPA and p53 levels assayed in cytosols by means of the immunoluminometric technique (LIA) were 0.31 and 0.20 ng mg(-1) of protein respectively. In univariate analysis, high levels of uPA and p53 were associated with shorter disease-specific survival, disease-free interval, and distant recurrence-free interval. The 5-year survival rates were 95.5% among patients with uPA values below the 20th percentile, and 77.5% in those with values above the 80th percentile. The 5-year survival rates were 91.0% in patients with p53 values below the 20th percentile, and 77.6% in those with values above the 80th percentile. In multivariate analysis, the risk of disease-related death increased with uPA levels after adjustment for tumour size, histological grade, lymph node involvement, and estrogen receptor status. A high level of uPA was also related to a shorter disease-free interval and distant recurrence-free interval. In node-negative patients, a high level of uPA remained strongly related to the three outcomes. When adjusted for other prognostic factors, p53 was no longer significantly related to the outcomes. Given its rapidity and simple application to routinely prepared cytosols, this LIA may be useful for evaluating the prognostic impact of uPA in primary breast cancer, particularly in node-negative patients. According to our results, the prognostic value of p53 accumulation is limited when uPA is included in multivariate analysis.
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PMID:Prognostic value of uPA and p53 accumulation measured by quantitative biochemical assays in 1245 primary breast cancer patients: a multicentre study. 1040 64

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in patients previously operated on for T1-T2 N-M0 breast cancer. During the trial, blood samples were collected at baseline and on a yearly basis from most of the patients. Evaluation of drug and retinol concentrations by HPLC assay has been performed for all the samples to obtain 4-HPR pharmacokinetic information as well as information on the effect of 4-HPR in lowering retinol plasma levels. The most important criteria for validation and quality control of the HPLC assay are summarized in order to provide a guide and practical recommendations for analytical procedures to be performed during prevention trials. Studies have been performed on subsets of patients participating in the trial in order to identify circulating biomarkers predictive of breast cancer. Evidence has been obtained on a lowering effect of 4-HPR on biologically active IGF-I only in premenopausal women. This was due to a decrease of IGF-I, associated with a trend to an increase in IGF-I binding protein 3 (IGFBP-3). An interim analysis of the ongoing trial indicates that 4-HPR reduces the incidence of contralateral breast cancer only in premenopausal women. Analyses of total and unbound IGF-I are being performed on plasma samples collected at baseline and during intervention from women < or = 50 years old. The relationship between the incidence of a second breast cancer and the changes in IGF-I plasma levels will be assessed in order to validate IGF-I as a surrogate end point of contralateral breast cancer. The preliminary results of other studies on the effects of 4-HPR on tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), and urokinase plasminogen activator (uk-PA) and on the relevance of circulating p53 antibodies with relapse will be also presented.
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PMID:Quality control for HPLC assay and surrogate end point biomarkers from the fenretinide (4-HPR) breast cancer prevention trial. 1076 18

Overexpression of urokinase plasminogen activator (uPA) and its receptor (uPAR) has been well documented in a wide variety of tumor cells. In breast cancer, expression of uPA/uPAR is essential for tumor cell invasion and metastasis. However, the mechanism responsible for uPA/uPAR expression in cancer cells remains unclear. In the studies reported here, we show that endogenous p38 MAPK activity correlates well with breast carcinoma cell invasiveness. Treatment of highly invasive BT549 cells with a specific p38 MAPK inhibitor SB203580 diminished both uPA/uPAR mRNA and protein expression and abrogated the ability of these cells to invade matrigel, suggesting that p38 MAPK signaling pathway is involved in the regulation of uPA/uPAR expression and breast cancer cell invasion. We also demonstrated that SB203580-induced reduction in uPA/uPAR mRNA expression resulted from the de- stabilization of uPA and uPAR mRNA. Finally, by selectively inhibiting p38alpha or p38beta MAPK isoforms, we demonstrate that p38alpha, rather than p38beta, MAPK activity is essential for uPA/uPAR expression. These studies suggest that p38alpha MAPK signaling pathway is important for the maintenance of breast cancer invasive phenotype by promoting the stabilities of uPA and uPAR mRNA.
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PMID:Urokinase plasminogen activator/urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p38alpha mitogen-activated protein kinase activity. 1076 65

Inhibition of urokinase plasminogen activator (uPA) has been shown to suppress cancer cell invasion and metastasis in the laboratory setting by numerous investigators. Most studies have used murine cell lines implanted in syngeneic rodents or transfected human cell lines grown in immunocompromised laboratory hosts. In this study using Matrigel invasion chambers and two separate uPA inhibitors, amiloride and B428, the invasive capacity of unaltered human breast cancer cells was significantly suppressed. Cell proliferation was also suppressed to a lesser degree. These findings suggest that uPA inhibition may be a valid clinical approach to the control of the invasion and metastasis of human cancers.
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PMID:Suppression of the invasive capacity of human breast cancer cells by inhibition of urokinase plasminogen activator via amiloride and B428. 1082 46

Migration studies suggest that the high incidence of postmenopausal breast cancer in Western women is related mainly to epigenetic factors. Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) also appears to involve environmental rather than genetic factors, and a role has been postulated for metabolic-endocrine changes related to the Western lifestyle. Protein kinase C (PKC) is important in cell signal transduction, and laboratory studies show that PKC stimulates the activities of urokinase plasminogen activator, matrix metalloproteinases and cell adhesion molecules, all of which are known to increase invasiveness in human mammary cancer cell lines. In rodents, the activity of PKC in tissue cells is enhanced by insulin, and PKC isoenzymes have been shown to stimulate the development of hyperinsulinaemic insulin resistance in rodents. Clinically, hyperinsulinaemia and the concomitant increase in circulating levels of free oestradiol and bioactive insulin-like growth factor 1 (IGF1) are each confirmed markers of high risk for breast cancer in women. Lesions of DCIS show evidence of regression with mammary involution, but it is postulated that this may be opposed by the concomitants of hyperinsulinaemic insulin resistance. The prevalence of the latter is increasing in Western populations, and a combination of high IGF1 and low IGF-binding protein 3 concentrations has been associated with the presence of DCIS lesions in premenopausal women. Measures that enhance insulin sensitivity in such women may reduce the risk of progression in DCIS lesions, and a clinical trial is proposed to test the hypothesis.
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PMID:Biological mechanisms in breast cancer invasiveness: relevance to preventive interventions. 1083 May 73

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

Increased urokinase plasminogen activator (u-PA) production is associated with tumor invasion and metastasis in several malignancies, including breast cancer. The mechanisms underlying constitutive u-PA expression are not well understood. We examined the relationship between the signal strength of the ERK pathway and the level of u-PA expression in the metastatic human breast cancer cell line MDA-MB-231. Treatment with the MEK1 inhibitor PD98059 resulted in decreased ERK1/2 phosphorylation and decreased u-PA mRNA and protein expression. Inhibition of ERK1/2 activity also led to decreased cell proliferation and to decreased cyclin D1 expression. Less than 5% of total ERK1/2 was phosphorylated in exponentially growing MDA-MB-231 cells, and ERK1/2 activity could be stimulated by okadaic acid. Okadaic acid did not stimulate u-PA expression, but induced strong expression of the cdk-inhibitor p21Cip1. These findings suggest that ERK1/2 signaling is tuned to a level which results in high u-PA expression and rapid cell proliferation.
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PMID:ERK signalling in metastatic human MDA-MB-231 breast carcinoma cells is adapted to obtain high urokinase expression and rapid cell proliferation. 1091 9

The urokinase plasminogen activator (uPA) system has been widely associated with the development of breast carcinoma. However, the role of the urokinase pathway in the development of osseous breast cancer metastases has been largely overlooked. We studied the expression of uPA, urokinase plasminogen activator receptor (uPAR)- and plasminogen activator inhibitor type-1 (PAI-1) in human breast carcinomas and their bone metastases, using in situ hybridisation. Studies were performed using paraffin-embedded tissue from 13 ductal carcinomas, 23 invasive ductal carcinomas, five normal breasts and 25 bone metastases. The majority of the tumours examined expressed low to moderate levels of uPA mRNA and low to high levels of uPAR and PAI-1 mRNA, which was predominantly localised to the epithelial tumour cells. There was slight over-expression of uPA and PAI-1 mRNA and a marked increase in uPAR mRNA expression in the malignant tumours compared with benign tissue. Overall, uPAR and PAI-1 mRNA expression was found to be more variable than uPA mRNA, suggesting a possible role of the receptor and inhibitor in the regulation of uPA activity. Increased alpha1(I) procollagen (COL) and osteopontin (OPN) mRNA expression was detected, primarily in the stromal cells, in malignant tumours compared with the benign tissue. The increased expression of the components of the uPA system on the epithelial tumour cells may account for the activation of the proteolytic cascade that occurs during breast cancer metastasis to bone. Furthermore, the over-expression of COL and OPN suggests a possible interaction between these matrix proteins and the uPA system.
Breast Cancer Res Treat 2000 May
PMID:Urokinase plasminogen activator system gene expression is increased in human breast carcinoma and its bone metastases--a comparison of normal breast tissue, non-invasive and invasive carcinoma and osseous metastases. 1093 85

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

Heregulin-beta1, which binds human epidermal growth factor receptors 3 and 4, promotes motility and invasiveness of breast cancer cells. Considering the established role of urokinase plasminogen activator (uPA) and its receptor (uPAR) in invasion, this study was undertaken to explore the role of heregulin-beta1 in regulating uPA and uPAR in breast cancer invasion. The stimulation by heregulin-beta1 of noninvasive human breast cancer MCF-7 cells induced the expression of uPA mRNA, protein, and its plasminogenic activity. This uPA mRNA expression was blocked by a transcriptional inhibitor, actinomycin D, and does require de novo protein synthesis for its optimal induction in MCF-7 cells, but not in mouse mammary epithelial HC11 cells. Heregulin-beta1 also induced the expression of uPAR mRNA and protein in an actinomycin D-sensitive manner and cycloheximide superinduced the uPAR mRNA. Heregulin-beta1-stimulated signaling initiated the transcription from uPA- and uPAR-promoters. These results suggest that heregulin-beta1 regulation of breast cancer cell invasion may be mediated in part through the up-regulation of uPA and uPAR.
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PMID:Heregulin regulation of urokinase plasminogen activator and its receptor: human breast epithelial cell invasion. 1119 94


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