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 aim of this study was to evaluate c-erbB-2 overexpression by means of a quantitative biochemical technique in 488 primary breast cancer patients with long-term follow-up (median, 10 years) and its relation to other biochemical prognostic factors (uPA, p53, and epidermal growth factor receptor) and adjuvant therapy. High levels of c-erbB-2 (>500 IU/mg protein) were associated with estrogen receptor (ER) and progesterone receptor negativity, high histoprognostic SBR grade and high levels of uPA and p53. Univariate analyses showed shorter metastasis-free survival (MFS) and overall survival (OS) in patients whose tumors overexpressed c-erbB-2 in the overall population, in subgroups defined by ER and uPA status, and in patients with positive pathological nodal status, SBR grade II, progesterone receptor, and p53-negative tumors. Patients with ER-positive, c-erbB-2-positive tumors had a shorter MFS and OS than those patients with c-erbB-2-negative tumors. No difference was observed between adjuvant-treated and untreated patients (chemotherapy and/or hormone therapy) in the c-erbB-2-negative subgroup. There was a trend toward a longer short-term MFS in c-erbB-2-positive patients treated with chemotherapy, whereas an opposite effect was observed with hormone therapy. Cox multivariate analyses showed that high levels of c-erbB-2 negatively influenced MFS in the overall population as well as in node-positive patients and in tamoxifen-treated patients, along with pN and uPA. Results for OS were comparable with those obtained for MFS. These results suggest that c-erbB-2 overexpression in breast cancer may be a better predictor of the response to tamoxifen than is ER status alone.
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PMID:Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis. 1115 29

We examined the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival of breast cancer patients. The study included 342 axillary lymph node-negative and -positive primary breast cancer patients with a median follow-up of 67 months. Using a newly established ELISA, the levels of preformed uPA-PAI-1 complex were measured in tumor tissue extracts and analyzed with respect to total uPA, total PAI-1, and clinicopathological parameters, including survival. uPA-PAI-1 complex comprised a minor, variable fraction of both total uPA and PAI-1 levels. The complex levels were higher in node-negative tumors than in node-positive tumors and higher in small and low-grade tumors (all, P < or = 0.002). The tumor levels of complex, uPA, and PAI-1 were all associated with survival; high complex levels predicted longer recurrence-free survival (P = 0.03) and overall survival [OS (P = 0.005)], whereas high uPA or PAI-1 levels significantly predicted shorter survival. In multivariate Cox analysis, the only parameters that independently predicted survival were total PAI-1 level and lymph node status for recurrence-free survival and OS and, additionally, steroid hormone receptor status and grade for OS. This is the first demonstration of a relationship between uPA.PAI-1 complex tumor level and patient survival. However, total PAI-1 level showed superior prognostic power. Additional studies are needed to understand the relationship of these parameters to cancer biology and to assess the clinical utility of the uPA PAI-1 complex.
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PMID:The complex between urokinase and its type-1 inhibitor in primary breast cancer: relation to survival. 1115 92

Disseminated tumor cells are detected frequently in bone marrow, peripheral blood, and cytokine-mobilized peripheral blood cell products of women undergoing high-dose therapy for breast cancer. Several attempts were made to purge autografts from contaminating cancer cells; however, the biological and clinical impact of these contaminations has not been clarified so far. Expression of distinct phenotypes is a surrogate marker for metastatic behavior of cancer cells. The expression of the urokinase-like plasminogen activator receptor seems to be a factor of high importance. It is not expressed by normal mammary tissue. Disseminated cancer cells from marrow, blood, and stem cell products have been investigated by double-stain technique for urokinase-like plasminogen activator receptor (uPA-R) expressing cytokeratin-positive cells. uPA-R(+)/CK(+) cells could be found in all qualities of samples; however, significantly less in G-CSF-mobilized peripheral blood stem cells compared to samples of other provenance (p = 0.02). It can be concluded that epithelial cells of malignant phenotype occur in blood, marrow, and autografts of breast cancer patients. Populations of disseminated tumor cells are phenotypically heterogeneous. Reduced uPA-R expression on cancer cells from leukapheresis samples might suggest a less aggressive nature of these cells compared to disseminated cells found in bone marrow. Furthermore, the data suggest that the phenotype of tumor cell contamination in leukapheresis products differs significantly from those of disseminated cancer cells in bone marrow or blood.
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PMID:Urokinase-like plasminogen activator receptor expression on disseminated breast cancer cells. 1127 67

Using Northern blot analysis we have measured the co-expression of the matrix metalloprotease MMP-9, plasminogen activator urokinase type (uPA) and its receptor (uPAR) mRNAs in 81 biopsies of breast carcinomas with the objective of analyzing the impact of these factors on the overall survival probability of the patients (median follow-up time: 4 years). Individual mRNA levels of either uPA or uPAR showed parallel variations with MMP-9 mRNA, suggesting a coordinate transcription of these markers. When median values were used as cutoff points to discriminate between high and low factor expression, no association was found with patient outcome and MMP-9 or uPA mRNA distribution. However, increased uPAR mRNA levels were associated with poor prognosis (p = 0.01). The combination of MMP-9 and uPAR mRNA measurements has not enhanced prognostic information compared to information supplied by the receptor alone (p = 0.01). The combination of MMP-9 and high levels of uPA mRNA led to a significant association with poor outcome (p = 0.03). Multivariate analysis supported the notion that increased uPAR mRNA production in primary breast cancer may be a predictor of overall survival.
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PMID:Prognostic significance of the combined expression of matrix metalloproteinase-9, urokinase type plasminogen activator and its receptor in breast cancer as measured by Northern blot analysis. 1128 58

The plasminogen activator inhibitor type-1 (PAI-1) is a multifaceted proteolytic factor. It not only functions as an inhibitor of the protease uPA (urokinase-type plasminogen activator), but also plays an important role in signal transduction, cell adherence, and cell migration. Thus--an apparent paradox considering its name--although it inhibits uPA during blood coagulation, it actually promotes invasion and metastasis. In the early 1990s, clinical evidence associated elevated PAI-1 levels in tumor tissue with poor clinical outcome in primary breast cancer. These clinical data have since been supported by experimental evidence that the concerted action of uPA, its cell surface receptor uPA-R, and PAI-1 facilitates invasion and metastasis. The strong prognostic impact of PAI-1 in primary breast cancer has been validated by international research groups assessing fresh tumor tissue extracts by ELISA. There is clinical evidence that high-risk patients with elevated PAI-1 in their tumor benefit from adjuvant systemic therapy. uPA also has a strong prognostic impact in primary breast cancer. In node-negative breast cancer, risk-group selection for adjuvant systemic therapy based on tumor levels of both PAI-1 and uPA is close to routine clinical use. Also in other malignancies such as ovarian, esophageal, gastric, colorectal or hepatocellular cancer, elevated PAI-1 is associated with tumor aggressiveness and poor patient outcome. This abundant clinical evidence implicating PAI-1 as a key factor for tumor invasion and metastasis renders it a promising target for tumor therapy. Novel therapeutic approaches targeting the PAI-1/uPA interaction are already in pre-clinical testing.
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PMID:Clinical relevance of the plasminogen activator inhibitor type 1--a multifaceted proteolytic factor. 1145 16

We reported previously that endogenous p38 MAPK activity is elevated in invasive breast cancer cells and that constitutive p38 MAPK activity is important for overproduction of uPA in these cells (Huang, S., New, L., Pan, Z., Han, J., and Nemerow, G. R. (2000) J. Biol. Chem. 275, 12266-12272). However, it is unclear how elevated endogenous p38 MAPK activity is maintained in invasive breast cancer cells. In the present study, we found that blocking alpha(v) integrin functionality with a function-blocking monoclonal antibody or down-regulating alpha(v) integrin expression with alpha(v)-specific antisense oligonucleotides significantly decreased the levels of active p38 MAPK and inhibited cell-associated uPA expression in invasive breast cancer MDA-MB-231 cells. These results suggest a function link between alpha(v) integrin, p38 MAPK activity, and uPA expression in invasive tumor cells. We also found that vitronectin/alpha(v) integrin ligation specifically induced p38 MAPK activation and uPA up-regulation in invasive MDA-MB-231 cells but not in non-invasive MCF7 cells. Finally, using a panel of melanoma cells, we demonstrated that the cytoplasmic tail of alpha(v) integrin subunit is required for alpha(v) integrin ligation-induced p38 MAPK activation.
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PMID:Alpha(v) integrin, p38 mitogen-activated protein kinase, and urokinase plasminogen activator are functionally linked in invasive breast cancer cells. 1160 83

We have recently shown that either exogenous or endogenous, transfected OPN induces both uPA expression and increased invasiveness of 21 PT (non-tumorigenic) and 21 NT (tumorigenic) human mammary epithelial cells. Here we asked whether uPA contributes functionally to the increased invasiveness of these cells. The most invasive OPN-transfected cells were assessed for migration through Matrigel in transwell assays, in the presence or absence of various blocking antibodies and uPA inhibitors. Antibodies to both uPA and uPA receptor (uPAR) were shown to significantly inhibit cell invasion, as did the uPA inhibitors (plasminogen activator inhibitor-1 [PAI-1], p-aminobenzamidine [PABN], aprotinin, and amiloride). Both anti-uPA and anti-uPAR antibodies inhibited invasion to a level comparable to that of the control vector transfected cells. In contrast, non-specific IgG showed no antiinvasive effect. Cell migration experiments performed with the parental cell lines in the presence or absence of anti-uPA or anti-uPAR antibodies showed that uPA is also required for migratory responsiveness to exogenous OPN. These data thus provide direct evidence that OPN-induced invasion and migration of these cells requires uPA.
Breast Cancer Res Treat 2001 Dec
PMID:Osteopontin(OPN)-induced increase in human mammary epithelial cell invasiveness is urokinase (uPA)-dependent. 1180 83

The independent prognostic value of protease uPA and its inhibitor PAI-1 for survival in breast cancer patients is firmly established. However, there is very little data on the prognostic value of serine proteases and their inhibitors for locoregional recurrence in breast cancer. The prognostic value of PAI-1 for local control in a group of 766 patients treated at our institute with either breast conserving treatment or modified radical mastectomy was evaluated. The locoregional recurrence-free survival (LRFS) of patients with PAI-1 values above the median value was significantly worse than that of patients with PAI-1 values below the median value (log-rank; p=0.0078). In multivariate analysis PAI-1 levels proved to be of independent statistical significance for LRFS (p=0.0401, relative risk 2.28, 95% confidence interval 1.04-5.02). The independent prognostic value of PAI-1 for metastasis-free survival and overall survival was also confirmed. In addition, our data suggest that PAI-1 antigen levels in tumor tissue might be of prognostic value for survival after locoregional recurrence (log-rank; p=0.0618). According to our findings, PAI-1 levels could be used as a biological marker that could facilitate the identifation of patients with a higher risk of local relapse already at the time of primary treatment. These patients should then be offered more aggressive treatment.
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PMID:Prognostic significance of plasminogen activator inhibitor-1 in breast cancer, with special emphasis on locoregional recurrence-free survival. 1193 84

Osteopontin (OPN) is a secreted, integrin-binding protein which has been implicated in cancer, as well as other pathologies and some aspects of normal development. Here we focus on the role of OPN in breast cancer. We describe studies that have shown that OPN plays a role in normal mammary gland development as well as in progression of breast cancer. We also summarize studies that have shown that OPN can play a functional role in malignancy of breast cancer. At least some of these effects are mediated by specific cell surface integrins (alpha(v)beta3 vs. alpha(v)beta1 and alpha(v)beta5) and lead to increased cell migration, activation of growth factor/receptor pathways (e.g. HGF and EGF), and increased proteolytic enzyme activity (e.g. uPA). We also summarize clinical studies that show that OPN levels in tumors and blood are elevated in women with metastatic breast cancer and may offer promise as prognostic markers in breast cancer.
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PMID:The role of osteopontin in breast cancer: clinical and experimental studies. 1201 31

Primary Breast Cancer, Urokinase-Type Plasminogen Activator, Inhibitors The aim of the study was to monitor urokinase plasminogen activator antigen concentrations and its type 1 (PAI-1) and type 2 (PAI-2) inhibitors in histologically defined forms of primary breast cancer and a comparison with these antigens levels in normal tissue. Another goal was a search for a relationship/or its lack/between the occurrence of the new generation markers of neoplastic disease and a presence/or absence/of lymph node metastases. U-PA, PAI-1 and PAI-2 antigen levels were determined by ELISA tests in protein extracts of breast cancer tissues. Among the studied breast tumors 32 specimens were ductal carcinomas, 15 specimens were lobular carcinomas and the remaining 13 were other rare histological forms. In comparison to the obtained values of u-PA antigen levels in normal tissue, the values in neoplastic tissues were elevated several times: 11-fold, 6-fold and 15-fold in ductal c., lobular c. and other rare neoplasms. The values of PAI-1 antigen levels were about 20-fold higher for all studied, histologically defined primary breast cancers. The greatest differences of PAI-2 antigen levels growth was observed in histologically defined primary breast cancer forms. It was augmented 10-fold, 40-fold and 20-fold, respectively, for ductal carcinoma, lobular carcinoma and rare forms of neoplasms. In various forms of invasive breast cancer and those without lymph node metastases the content of u-PA, PAI-1 and PAI-2 were also significantly elevated. Among the new generation of independent markers of the neoplastic process, PAI-2 seems to be the most reliable marker for the identification of primary breast cancer. The goal of the present study was to evaluate a possible combined prognostic value of the three major components of the u-PA system (u-PA, PAI-1 and PAI-2) in patients with defined histopathological forms of primary breast cancer.
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PMID:Antigen levels of urokinase type plasminogen activator and its inhibitors in primary breast cancer. 1206 42


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