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

Current research in the area of breast malignancies is focusing on identification of pathogenetic risk factors, chemoprevention, screening policies, local treatment modalities that minimize disfigurement, and improved adjuvant therapeutic and palliative systemic therapies. Although epidemiologic studies have produced contradictory results, oral contraceptive use before age 25 years and before 1st full-term pregnancy appears to increase the breast cancer risk. In need of thorough study is the safest form of estrogen replacement therapy in postmenopause. Screening programs aimed at early detection have been shown to reduce breast cancer mortality by 30% in women 50-69 years of age, but no preventive strategies have been identified for younger and older women. A trend toward breast-conserving primary therapy represents a major shift in this area. As long as the tumor is less than 4 cm in diameter and the resection margins are free of tumor, lumpectomy produces disease-free survival rates comparable to those obtained through total mastectomy. In node-positive patients, hormonal adjuvant systemic therapy is effective in postmenopausal women while chemotherapy is effective in premenopausal women. The data are insufficient to allow recommendations regarding adjuvant treatment of node-negative patients, whose overall survival rate is about 70%. In metastatic breast cancer, tamoxifen is the drug of choice for palliation. Prognostic factors currently under study include oncogene amplification, urokinase plasminogen activator level, expression of growth factors and growth factor receptors, proliferation parameters, mutations, and cathepsin D levels.
 ...
PMID:Breast malignancy. 187 98

Using confocal fluorescence microscopy with a monoclonal antibody, we have localized the receptor for urokinase plasminogen activator (uPAR) in MDA-MB-231 human breast cancer cells migrating into a reconstituted basement membrane. Patchy and polarized uPAR immunoreactivity was found at the cell membrane, and strong staining was found both in the ruffled border or leading edge of the cells and at pseudopodia penetrating into the membrane. Intracellular uPAR staining was localized in the paranuclear region and in rounded granule-like structures; some of these were identified as lysosomes by double staining for uPAR and the lysosomal enzyme cathepsin D. Urokinase plasminogen activator (uPA) activity has previously been shown to play a role in migration of cells into basement membranes, and it has been proposed that uPAR also is involved in this process. uPA is known to be internalized and degraded after complex formation with the inhibitor PAI-1. Lysosomal uPAR immunoreactivity may result from concomitant internalization of the receptor.
 ...
PMID:Confocal fluorescence microscopy of urokinase plasminogen activator receptor and cathepsin D in human MDA-MB-231 breast cancer cells migrating in reconstituted basement membrane. 751 99

Recent studies have shown that elevated levels of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) in breast cancer correlate with an increased risk of a reduced relapse-free survival time and shortened overall survival times. Urokinase PA and PAI-1 are independent prognostic indicators for breast cancer. The fact that plasminogen activators are indispensable for tube formation of microvascular cells and that they may induce angiogenesis in vitro strongly suggests a role for uPA and PAI-1 in tumour neovascularisation. Because macrophages and tumour cells produce uPA, we postulate a close collaboration between tumour cells and tumour-associated macrophages in angiogenesis. To investigate how uPA levels and macrophage counts in tumour tissue correlate with angiogenesis, we counted microvessels and determined uPA levels and macrophage content in 42 primary invasive breast carcinomas. Using light microscopy, we highlighted the vessels by staining their endothelium cells immunocytochemically for CD31 and factor VIII and the macrophages for CD68. After obtaining tumour tissue extracts, we determined the uPA and PAI-1 levels by ELISA. A positive correlation between microvessel density, vascular invasion, uPA level, macrophage content and proliferation rate was found.
 ...
PMID:Urokinase and macrophages in tumour angiogenesis. 754 26

Disregulation of urokinase plasminogen activator (uPA) was assessed in 134 breast cancer specimens. Overexpression of uPA was determined by immunohistochemistry using the specific monoclonal antibody, #394. Gene amplification was assessed by differential polymerase chain reaction, using primers designed to amplify a 111 bp segment of the uPA gene. Overexpression of uPA was detected in 33% of breast cancers, including 4 of 21 in situ carcinomas, 7 of 14 lobular and 2 of 10 tubular carcinomas. Overexpression of uPA did not correlate with the presence or absence of oestrogen receptors. uPA gene amplification was not detected in any cancer. We conclude that uPA gene amplification is not a major mechanism instigating uPA overexpression in breast cancer, and that overexpression is likely to be controlled by other mechanisms.
 ...
PMID:Disregulation of urokinase plasminogen activator gene in breast cancer. 769 59

Current evidence regarding the regulation of urokinase-dependent extracellular proteolysis indicates that plasminogen activation is a surface-associated process. We have compared the histological localization of urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) in breast cancer sections using a panel of monoclonal antibodies. First, the ability of six different anti-uPA monoclonal antibodies to recognize pro-uPA, uPA, and in vitro-formed complexes of uPA with either soluble uPAR or with plasminogen activator inhibitor type 1 was compared. Then the reactivity of the anti-uPAR antibodies was tested, and the occurrence of an uPA receptor of about M(r) 55,000 in samples from breast carcinoma was assessed by immunoprecipitating the uPA receptor from an in vitro 125I-labeled tumor extract. Immunocytochemical data from adjacent sections of 10 tumor specimens showed that antibodies recognizing free and bound uPA mostly stain the cytoplasm and the membrane of epithelial tumor cells in confined areas of the tumor and some fibroblast-like stromal cells. Acid pretreatment of tumor sections, which removes receptor-bound uPA, causes a strong reduction of the immunocytochemical reactivity of epithelial tumor cells, whereas staining of fibroblast-like cells is not considerably affected. Consistent with these results, epithelial tumor cells were mostly unreactive to anti-uPAR antibodies unless pretreated with acidic buffer, whereas fibroblast-like stromal cells showed a faint but acid-resistant staining with all anti-uPARs. In conclusion, these results show that occupied uPA receptors are definitely present on the membrane of epithelial tumor cells and suggest the occurrence of uPA-uPAR-dependent proteolytic activity on the surface of breast cancer cells.
 ...
PMID:Tissue distribution of soluble and receptor-bound urokinase in human breast cancer using a panel of monoclonal antibodies. 792 78

There is ample evidence that the protease urokinase plasminogen activator (uPA) plays a role in invasion and spread of tumours. Several publications suggest its biochemical measurement in tumour cytosols to be of prognostic significance in breast carcinomas. Our study set out to determine whether the immunohistochemical detection of uPA in formalin-fixed, paraffin-embedded primary breast cancer tissues is of prognostic relevance. We tested 269 surgical specimens of primary ductal infiltrating carcinoma immunohistochemically using a modified avidin-biotin method. Some 57% of carcinoma specimens yielded specific positive staining in tumour cells. Detection of uPA correlated to tumour grade (P = 0.04), and to the detected level of the proliferation marker PCNA (P = 0.002), but not to patients' age or menopausal status, tumour size, nodal or steroid receptor status (P > 0.05). At median 68 months' follow-up, 34% of patients had experienced tumour relapse and 28% had died from cancer. Clinical course was correlated significantly to tumour size, tumour grade, nodal and steroid hormone receptor status (P < 0.05). Immunohistochemical detection of uPA, however, could not be demonstrated to be of any prognostic significance with regard to relapse-free or overall survival (P > 0.05) in the total study group or in the N0 (n = 120) and N + (n = 144) subgroups, regardless of whether univariate or multivariate analysis was applied.
 ...
PMID:[Prognostic value of immunohistochemical determination of urokinase plasminogen activator in primary breast cancers]. 857 May 58

The lysosomal protease Cathepsin D and the serine protease urokinase plasminogen activator (uPA) are suspected to indicate poor prognosis in primary breast carcinoma. We tested Cathepsin D and uPA immunohistochemically in 281 surgical specimens of primary ductal infiltrating breast carcinomas. Staining was evaluated, taking intracytoplasmic immunoreactions into account, in tumour cells and tumour infiltrating macrophages. Positivity was established in 48.4% and 58.0% of tissue samples for cathepsin D and uPA respectively (co-expression: 67.6%). In patients with cathepsin D- or uPA-positive tumours, relapses were more frequent and disease-free survival was shorter irrespective of nodal status, receptor status or menopausal status, (median observation time 74 months). However, this trend was statistically significant only for cathepsin D. With stepwise cox regression analysis, borderline significance (p = 0.07) was calculated for cathepsin D only in node-negative patients. The combination of cathepsin D with uPA measurements did not enhance its prognostic value. Immunohistochemical detection of Cathepsin D could potentially be used to identify patients with poor prognosis in the group of node negative breast cancer patients.
 ...
PMID:Comparative prognostic value of Cathepsin D and urokinase plasminogen activator, detected by immunohistochemistry, in primary breast carcinoma. 868 92

We have compared by RNA in situ hybridisation on serial cryo-sections the distribution of cathepsin D (cathD), stromelysin 3 (strom-3), and urokinase plasminogen activator (UPA) gene expression in different tissues of human benign and malignant mammary tumors. Cath-D expression was found to be higher in adenocarcinomas compared to non-tumoral glands. The cath-D RNA was located in mammary epithelial cancer cells rather than in fibroblasts, indicating that the cath-D gene was overexpressed in cancer cells, where the corresponding protein determined by immunohistochemical staining had been shown to be accumulated (E Roger et al., Human Pathol 25: 863-871,1994). In contrast strom-3 RNA in adjacent tissue sections used as a control of tissue localisation was mostly expressed in peritumoral fibroblasts rather than in cancer cells confirming previous results of Basset et al. and validating our methodology. UPA RNA was detected both in tumor cells and in stromal cells. In benign lesions the 3 protease RNAs were mostly found in epithelial cells. Stromal cells expressed UPA RNA in 5 of 7 lesions, cath-D and strom-3 in only one sample. We conclude that in breast cancer patients, cath-D gene expression is increased in epithelial mammary cancer cells at the RNA level as well as at the protein level, suggesting an altered transcriptional regulation. In non malignant lesions, the distribution was different with a predominant distribution in epithelial mammary cells for the 3 protease messenger RNA.
Breast Cancer Res Treat 1996
PMID:Cellular localisation by in situ hybridisation of cathepsin D, stromelysin 3, and urokinase plasminogen activator RNAs in breast cancer. 886 40

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

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


1 2 3 4 5 6 7 8 9 10 Next >>