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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of urokinase-type plasminogen activator and its receptor correlates with metastatic capacity in breast cancer. In this study we show that the urokinase/urokinase receptor-overexpressing, metastatic human breast cancer cell line MDA-MB-231 (1) bound significantly more cell-surface plasminogen in a lysine-dependent manner and (2) was capable of generating large amounts of plasmin compared with the non-metastatic cell lines MCF-7 and T-47D. In addition, distinct plasminogen binding proteins were detected in the plasma membranes of the cell lines, suggesting heterogeneity of binding proteins. Plasminogen binding was analysed using a combination of dual-colour fluorescence flow cytometry and ligand histochemistry (for comparative and cellular localization of ligand binding), and fluorimetry (for Scatchard analysis). Apart from revealing the greater plasminogen binding capacity of MDA-MB-231 cells, flow cytometry and histochemistry also revealed that, in all three cell lines, non-viable or permeabilized cells bound significantly more plasminogen in a lysine-dependent manner than viable or non-permeabilized cells. Viable MDA-MB-231 cells bound plasminogen with moderate affinity and high capacity (Kd = 1.8 microM, receptor sites per cell 5.0 x 10(7). Our results indicate that differences in cell surface-specific plasminogen binding capacity between cell lines may not be detectable with binding techniques that cannot distinguish between viable and non-viable cells.
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PMID:Increased plasminogen binding is associated with metastatic breast cancer cells: differential expression of plasminogen binding proteins. 963 33

Complexes between urokinase-type plasminogen activator (uPA) and its receptor (uPAR) were assessed in plasma and serum from 39 breast cancer patients and from 20 healthy individuals, applying a recently developed enzyme-linked immunosorbent assay (ELISA) for the analysis of these complexes in tumor tissue extracts. The assay is based on a combination of rabbit polyclonal anti-uPA antibodies for catching and a mouse anti-uPAR monoclonal antibody (MAb) for detection. The specificity of the assessment of uPA:uPAR complexes was verified by simultaneous analysis of the individual blood samples in corresponding non-sense ELISA formats, in which either the anti-uPA catching antibody or the anti-uPAR detecting antibody was substituted with an irrelevant antibody. Assessment of native uPA:uPAR complexes was ascertained by demonstrating the absence of any de novo formation of uPA:uPAR complexes in plasma and serum during the sample incubation step in the ELISA, as verified by the use of a peptide antagonist for uPAR. Plasma and serum samples contained almost identical levels of uPA:uPAR complexes. The levels of uPA:uPAR complexes were found to be significantly lower in serum from breast cancer patients compared to the serum of healthy donors, while the levels of (total) uPAR in plasma from breast cancer patients were significantly higher than in plasma from the healthy controls. In addition, the free, uncomplexed uPAR levels, estimated by subtraction of uPA:uPAR complex levels from (total) uPAR levels, were significantly elevated in plasma as well as in serum from breast cancer patients compared to healthy individuals. The uPA:uPAR complex levels were highly comparable to the uPA levels analyzed in the same plasma and serum samples, indicating that most if not all of the uPA present in these samples is complexed with uPAR.
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PMID:Complexes between urokinase-type plasminogen activator and its receptor in blood as determined by enzyme-linked immunosorbent assay. 965 May 59

Urokinase-type plasminogen activator (uPA) is a potentially important prognostic factor in breast cancer for identifying patients at high risk of recurrence. This retrospective study assessed two enzyme-linked immunosorbent assay (ELISA) methods measuring uPA antigen levels in 499 primary breast cancer cytosols. Both uPA methods were applied to cytosols used routinely for oestrogen (ER) and progesterone (PgR) receptor assays. uPA was determined using a classical ELISA method (Imubind; American Diagnostica) and a novel automatic immunoluminometric assay (Lia; Sangtec Medical). The uPA Imubind method revealed about twice as much uPA antigen (median 0.75 ng mg(-1) protein) as the uPA Lia method (median 0.38 ng mg(-1) protein). The correlation coefficient between the two methods was acceptable (r = 0.81), but the two techniques are not interchangeable. Univariate analyses confirmed the poor outcome of patients whose tumours contained large amounts of uPA, regardless of the technique used. Multivariate analyses showed that uPA Imubind and uPA Lia values were both strong independent prognostic factors.
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PMID:Prognostic value of urokinase plasminogen activator in primary breast carcinoma: comparison of two immunoassay methods. 965 68

To understand the hormonal regulation of the components of the plasminogen-plasmin system in human breast cancer, we examined the oestradiol (E2) regulation of plasminogen activators (PAs), namely urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1) and uPA receptor (uPAR), in our model system. We used stable transfectants of the MDA-MB-231 human breast cancer cells that express either the wild-type (S30 cells) or the mutant 351asp-->tyr oestrogen receptor (ER) (BC-2 cells). Northern blot analysis showed that there was a concentration-dependent down-regulation of uPA, tPA and PAI-1 mRNAs by E2. In contrast, uPAR mRNA was not modulated by E2. The pure anti-oestrogen ICI 182,780 was able to block E2 action, indicating that the regulation of these genes is ER mediated. The E2 also inhibited the expression and secretion of uPA, tPA and PAI-1 proteins as determined by enzyme-linked immunosorbent assay (ELISA) in cell extracts (CEs) and conditioned media (CM). Zymography of the CM confirmed the inhibitory effect of E2 on uPA activity. Thus, we now report the regulation of uPA, PAI-1 and tPA by E2 in both mRNA and protein levels in ER transfectants. The association between down-regulation of the uPA by E2 and known E2-mediated growth inhibition of these cells was also explored. Our findings indicate that down-regulation of uPA by E2 is an upstream event of inhibitory effects of E2 on growth of these cells as the addition of exogenous uPA did not block the growth inhibition by E2.
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PMID:Oestradiol regulation of the components of the plasminogen-plasmin system in MDA-MB-231 human breast cancer cells stably expressing the oestrogen receptor. 966 56

The levels of several tumor-associated proteases, including plasminogen activators (PA), are elevated in many malignant tumors compared to their benign tumor counterparts. Extracellular matrix degradation mediated by PA may facilitate tumor cell invasion and metastasis. In this study, the anti-proliferative activities of anti-urokinase-type plasminogen activator monoclonal antibodies (anti-UK MAbs) against human breast cancer cell lines were tested. Immunofluorescence studies localized urokinase (UK) on the surfaces of breast cancer cells. Inhibition studies showed that anti-UK MAb concentrations exerted 50% inhibition of 3H-thymidine uptake by human breast cancer cell lines; CRL-1500 and CRL-1504 were 5.6 x 10(-9)-1.82 x 10(-13) and 3.16 x 10(-10)-3.54 x 10(-12) M, respectively. Anti-UK MAbs exhibited little effect (10-20%) on normal human lymphocyte and liver cell lines. Dye exclusion indicated that anti-UK MAbs had a potent cytolytic effect on human breast cancer cells. Taken together, these results demonstrated the potential of anti-UK MAbs to be a valuable reagent for cancer immunotherapy and anti-metastatic therapy.
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PMID:Anti-urokinase-type plasminogen activator monoclonal antibodies inhibit the proliferation of human breast cancer cell lines in vitro. 967 32

The serine protease urokinase-type plasminogen activator (uPA) mediates cancer invasion and metastasis by binding to a cell surface receptor (uPA-R, CD87) on both tumor and stromal cells. In the present study we assessed uPA-R distribution in formalin-fixed, paraffin-embedded breast cancer specimens (n=50) and benign lesions (n=10) by immunohistochemistry employing a newly developed polyclonal chicken antibody to uPA-R (pAb HU277) in parallel with established monoclonal antibody (mAb) 3936 to uPA-R. In addition, uPA-R mRNA synthesis was investigated by in situ hybridization. In all of the sections analyzed, macrophage-like cells reacted with either antibody type. In 22 of the 50 cancer specimens, tumor cells reacted with pAb HU277 in contrast to mAb 3936 which only stained 9 of the 22 positive cases. Nevertheless, in 49 of the 50 cases, uPA-R mRNA was detected in cancer and in stromal cells by in situ hybridization suggesting posttranscriptional regulation of uPA-R expression in breast cancer cells. In 18 of 50 cases, uPA-R mRNA was also visualized in blood vessel lining endothelial cells by in situ hybridization and applying pAb HU277 in 14 of these 18 cases by immunohistochemistry. mAb 3936 did not stain any endothelial cells. pAb HU277 reacted with the breast gland epithelial cells of benign lesions as well, in contrast to mAb 3936 which did not. As for the cancer tissue, in benign lesions, endothelial cells were sporadically stained by pAb HU277. This antibody, but not mAb 3936, also stained myoepithelial cells in intraductal areas of invasive breast carcinoma. The results presented demonstrate the usefulness of pAb HU277 in locating uPA-R in tumor and normal cells with high sensitivity in formalin-fixed, paraffin-embedded breast tissue.
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PMID:Urokinase receptor localization in breast cancer and benign lesions assessed by in situ hybridization and immunohistochemistry. 968 86

The plasma urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator receptor (uPAR) levels were measured in healthy volunteers and breast cancer patients. In pre-menopause healthy females, blood was sampled weekly during one menstruation cycle and menstruation phases (follicular, ovulatory, luteal) were determined by FSH/LH levels. uPA, PAI-1, and uPAR levels were at the nadir during ovulatory phase. uPA level was highest at follicular phase while PAI-1 level was highest at luteal phase. In comparison between pre- and post-menopause states, uPA and uPAR levels were higher in post-menopause state while PAI-1 level was higher in pre-menopause state. In breast cancer patients, uPA, PAI-1, and uPAR positive rates were low when we use the menopause-state-unmatched cut-off points. As we adjusted the cut-off points by menopause states, the PAI-1 positivity increased mainly in post-menopause cancer patients. These findings suggest that there is a minor but possible sequential change of these molecules during menstruation cycle which might blur the pathological positivity in pre-menopause cancer patients. The pathological elevation of PAI-1 was well detected in post-menopause cancer patients, but this elevation did not correlate with tumor burden such as number of metastatic sites or metastatic location. In conclusion, adjustment of physiological changes of uPA, PAI-1, and uPAR is required in determining pathological elevation of the plasma levels in cancer patients, especially in females.
Breast Cancer Res Treat 1998 May
PMID:Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients. 969 10

Urokinase type plasminogen activator (uPA) and its inhibitors, plasminogen activator inhibitor type I (PAI-1) and type II (PAI-2), are supposed to be involved in the expression of the invasive and metastatic phenotype of cancer cells. However, clinical investigations on the prognostic significance of their levels in tumor tissue are difficult to realize because of the absence of a convenient method of measurement of these parameters. The aim of the present investigation was to set up a method allowing the measurement of these enzymes and of sex steroid receptor status in appropriate subcellular fraction(s) in conditions easily reproducible in routine. We found that a tissue homogenate prepared according to the method recommended [5] for current measurement of sex steroid receptors is appropriate for further distinct preparations. One aliquot is used for cytosol preparation; another can be treated by 2% Triton X-100 (vol/vol) and provide an extract containing the totality of uPA and PAI-1. The advantage of this procedure is that appropriate subcellular fractions can be derived from a unique homogenization step. Total uPA and PAI-1 are measured in a Triton extract with good performance as compared to previous investigations [4]. PAI-2 is measured in the same cytosol fraction used for sex steroid receptors and other parameters. Because of its simplicity and its high reliability, this method could be a useful tool in the investigation of uPA family proteases and analysis of their prognostic significance in early breast tumors.
Breast Cancer Res Treat 1998 May
PMID:Tissue extraction procedures for investigation of urokinase plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in human breast carcinomas. 969 96

In node-negative breast cancer, 70% of patients are cured by surgery alone and thus should be spared the necessity of systemic adjuvant treatment. Histomorphological and tumor biological prognostic factors may be employed to assess the patient's risk profile with regard to disease recurrence and death. To evaluate the relationship between tumor biological factors and the metastatic potential of primary breast cancer, proteolytic factors uPA, PAI-1, and cathepsin L, which are associated with tumor invasion and metastasis, were determined in breast cancer tissue extracts by ELISA and the values assessed by uni- and multivariate analysis as well as CART (classification and regression trees) in comparison with traditional prognostic factors. Cysteine protease cathepsin L, serine protease uPA, and the protease inhibitor PAI-1 were determined by ELISA in extracts of primary tumors of 103 node-negative breast cancer patients and values assessed by univariate and multivariate analysis in comparison with traditional prognostic factors (tumor size, steroid hormone receptor status, grading, vessel invasion, menopausal status). Median follow-up of patients still alive at time of follow-up was 56.5 months (range 34-88). PAI-1, cathepsin L, tumor size, grading, and steroid hormone receptor status but not uPA, vessel invasion, and menopausal status were of prognostic relevance for disease-free survival (univariate analysis). Multivariate analysis of disease-free survival (Cox proportional hazards model) disclosed PAI-1 (relative risk of 8.6, p = 0.0001) to be the only strong and statistically independent prognostic factor. By CART-analysis, however, the combination of PAI-1 (< or = 14 ng/mg protein) and cathepsin L (< or = 1,100 ng/mg protein) allowed the identification of a subgroup comprising 68% of the node-negative breast cancer patients having a very low risk of disease recurrence (2/70; incidence of 0.8% per year) versus the high-risk group with PAI-1 (> 14 ng/mg protein) and cathepsin L (> 1,100 ng/mg protein) showing an increased recurrence rate (14/33; incidence of 8.6% per year). We conclude that by the combined determination of PAI-1 and cathepsin L tumor levels low-risk node-negative breast cancer patients may be identified. These patients most probably will not benefit from systemic adjuvant therapy.
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PMID:Identification of low-risk node-negative breast cancer patients by tumor biological factors PAI-1 and cathepsin L. 970 80

Tumor biological factors uPA, PAI-1, cathepsin D, S-phase fraction (SPF), MIB1 (Ki-67), p53, and HER-2/neu were assessed in 100 node-negative breast cancer patients. Their prognostic impact on disease-free (DFS) as well as overall survival (OS) was compared to that of traditional factors tumor size, grading, and steroid hormone receptor status. Antigen levels of uPA, its inhibitor PAI-1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. SPF was determined by flow cytofluorometry, MIB1, p53, and HER-2/neu by immunohistochemistry in adjacent routinely formalin-fixed paraffin sections. Median follow-up in all patients still alive at time of analysis was 76 months. Univariate analysis determined PAI-1 (p = 0.0001), uPA (p = 0.0437), MIB1 (p = 0.0214), and SPF (p = 0.0248) as statistically significant prognostic factors for DFS. In contrast, tumor size, steroid hormone receptor status, grading, p53, HER-2/neu, and cathepsin. D failed to be of prognostic value. In multivariate analysis, including the statistically significant prognostic factors PAI-1, uPA, MIB1, and SPF, only PAI-1 (p = 0.0003, relative risk: 4.7) proved to be of independent statistical significance for DFS. Regarding OS, PAI-1 was the only statistically significant prognostic factor in univariate (p = 0.0001) as well as multivariate analysis (p = 0.0000, relative risk: 7.1). Thus, factors describing the invasive and metastatic capacity of tumor cells (uPA, PAI-1) and factors related to their proliferative activity (SPF, MIB1) provide valuable prognostic information in node-negative breast cancer patients.
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PMID:Prognostic impact of tumor biological factors on survival in node-negative breast cancer. 970 82


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