Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two types of gastric adenocarcinoma can be distinguished histopathologically: the diffuse and the intestinal type. Molecular pathology supports this theory by showing differences in the genetic pathways of both tumor types. In addition to known pathomorphological factors of prognosis, e.g., depth of tumor infiltration, number of lymph node metastases and resection margins, a few genes have been suggested to have prognostic impact in gastric carcinoma. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. Gene amplification and protein overexpression of the growth factor receptors c-erbB-2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. In addition, genetic instability is commonly seen. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited form of diffuse-type gastric cancer and could be used to identify individuals that are at high risk.
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PMID:Gastric adenocarcinoma: pathomorphology and molecular pathology. 1131 54

It has been suggested that uPA in cancer cells is up regulated by the p 185 kD form of the HER-2/neu oncogene. We elected to see if the extra cellular domain of HER-2/neu, the p 105 fraction, which is found in the circulation, has any regulatory influence on uPA or uPAR in those patients with NSCLC Levels of uPA, uPAR and p 105 HER-2/neu were determined in blood from age-matched controls and patients with advanced NSCLC. In the patients with NSCLC, samples were obtained before and following treatment. A large increase in both uPA and uPAR compared to controls was seen in the patients prior to treatment. The uPAR level post-treatment decreased from pre-treatment values, which is favorable. There was a significant increase in uPA and a decrease in HER-2/neu in the post-treatment time frame. Additionally, correlation analysis of circulating uPAR, uPA and HER-2/neu against each other in both the controls and treatment groups indicated no relationship. It appears that circulating uPA and uPAR are elevated in NSCLC patients. The up-regulation of uPA by HER-2/neu seen in lung cancer cells in vitro is apparently lost in the blood in vivo as is evidenced by the lack of correlation between them which is also true for the receptor as well.
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PMID:The circulating urokinase plasminogen activator (uPA) and its soluble receptor (suPAR) are not up-regulated by the circulating P105 fraction of the HER-2/neu proto-oncogene: in vivo evidence from patients with advanced non-small cell lung cancer (NSCLC). 1217 85

In a retrospective study of 488 women with primary breast cancer, after a median follow-up of 10 years, we sought interactions between disease-free survival (DFS) and overall survival (OS) and tumor antigen levels of two components of the plasminogen system, urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1, and the transmembrane growth factor receptor c-erbB-2. We used ELISAs (American Diagnostica, Greenwich, CT, USA) to quantify uPA and PAI-1 antigen levels in cytosols, and a double monoclonal antibody-based assay (EIA) (Ciba Corning Diagnostics, Alameda, CA, USA) to quantify c-erbB-2 in membrane extracts of the same tissues. Weak positive correlations were found between uPA and c-erbB-2 (r(s) = 0.146; p = 0.001) and between PAI-1 and c-erbB-2 (r(s) = 0.154; p < 0.001). In the overall population, using univariate analyses, c-erbB-2 overexpression and high uPA and PAI-1 antigen levels (> 300 IU/mg, > 1.40 ng/mg and > 5.53 ng/mg, respectively) were significantly associated with shorter DFS (p = 0.003, p < 0.001 and p < 0.001, respectively) and OS (p < 0.001 in all cases). Using multivariate analyses, PAI-1, node status and tumor size were independent predictors of DFS and c-erbB-2 was retained in the model only for OS. In the node-negative subgroup, PAI-1 was the strongest significant survival predictor both for OS (p = 0.003; HR 2.52) and DFS (p < 0.001; HR 2.39). This study shows that in primary breast cancer c-erbB-2 offers no additional prognostic information when uPA and/or PAI-1 are candidates in the multivariate analyses.
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PMID:Limited prognostic value of c-erbB-2 compared to uPA and PAI-1 in primary breast carcinoma. 1453 92

To study the molecular mechanism of inhibition of angiogenesis in HER-2/neu-overexpressing breast cancer by genistein, HER-2/neu negative expression breast cancer MCF-7 cells were transfected with HER-2/neu to establish HER-2/neu-overexpressing MCF-7 cells (named MCF-7/HER-2). Expression of vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), matrix metalloproteinase-2,9 (MMP-2,9) in MCF-7, MCF-7/HER-2 as well as genistein-treated MCF-7/HER-2 were measured by immunocytochemistry and Western blot. We found that the expression of VEGF, MMP-2,9 and uPA in MCF-7/HER-2 cells were highter than that in MCF-7 cells, those angiogenesis related factors expression in MCF-7/HER-2 cells significantly decreased after treatment with genistein. Genistein could inhibit expression of angiogenesis-related factors VEGF, MMP-2,9 and uPA in HER-2/neu-overexpressing breast cancer cells, and this may be part of molecular mechanism of its anti-angiogenesis in HER-2/neu-overexpressing breast cancer.
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PMID:[Effect of genistein on expression of angiogenesis related factors in HER-2/neu-overexpressing breast cancer cells]. 1532 30

The Ets family of transcription factors regulate expression of multiple genes involved in tumour progression. The aim of this study was to investigate the expression of Ets-1 in a large panel of human breast cancers and relate its levels to the parameters of tumour progression and metastasis. Using RT-PCR, Ets-1 mRNA was detected in 30 out of 42 (71%) fibroadenomas and 131 out of 179 (73%) primary breast carcinomas. Similarly, levels of Ets-1 mRNA were not significantly different in fibroadenomas and primary breast carcinomas. Using Western blotting, four forms of the Ets-1 protein were detected, that is, p33, p42, p51 and p52. Levels of both p51 and p52 but not p33 and p42 were present at significantly higher levels in the carcinomas compared to the fibroadenomas (for p51, P<0.007; for p52, P<0.02; Mann-Whitney U-test). Levels of p52, p51 and p33 correlated significantly with uPA protein levels (P<0.01), while only levels of p52 correlated significantly with HER-2/neu protein levels (P<0.01). Using immunohistochemistry, Ets-1 was found predominantly in tumour cells, but was also detected in some stromal cells surrounding tumour islands. We conclude that, while at the mRNA level, Ets-1 was found at similar levels in fibroadenomas and primary breast carcinomas, higher protein levels were detected in the cancers compared to the benign specimens. Since p52, p51 and p33 correlate with uPA levels, these forms of Ets-1 may play a role in breast cancer metastasis.
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PMID:Overexpression of the Ets-1 transcription factor in human breast cancer. 1633 4

Besides the traditional therapeutic options, treatment with antibodies specific for the receptor tyrosine kinase HER-2/neu has been established as a standard therapy in the clinical management of advanced breast cancer. Ongoing clinical studies focus on the improvement of application protocols in order to minimize side effects and evaluate the potential therapeutic benefit of anti-HER-2/neu antibodies in combination with conventional chemotherapy. Various similar strategies to target other tumour-associated antigens or proangiogenic factors with inhibitory antibodies are currently investigated in promising preclinical and clinical trials. In addition, research efforts are made to develop procedures to generate tumour-specific cellular immune responses in breast cancer patients. Therapeutic vaccination is, however, still at an early stage of development, despite encouraging results of animal studies. We summarise and discuss vaccination strategies with tumour-specific proteins or peptides, pulsed dendritic cells, and modified tumour cells as well as antibody-based therapeutic concepts to target HER-2/neu, EGF receptor, MUC-1, uPA/uPAR, and VEGF.
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PMID:Immunotherapy and cancer vaccines in the management of breast cancer. 1624

Urokinase-type plasminogen activator (uPA) binding to uPAR induces migration, adhesion, and proliferation through multiple interactions with G proteins-coupled receptor FPRL1, integrins, or the epidermal growth factor (EGF) receptor (EGFR). At least two forms of uPAR are present on the cell surface: full-length and cleaved uPAR, each specifically interacting with one or more transmembrane proteins. The connection between these interactions and the effects on the signaling pathways activation is not clear. We have exploited an uPAR mutant (hcr, human cleavage resistant) to dissect the pathways involved in uPA-induced cell migration. This mutant is not cleaved by proteases, is glycosylphosphatidylinositol anchored, and binds uPA with a normal K(d). Both wild-type (wt) and hcr-uPAR are able to mediate uPA-induced migration, are constitutively associated with the EGFR, and associate with alpha3beta1 integrin upon uPA binding. However, they engage different pathways in response to uPA. wt-uPAR requires both integrins and FPRL1 to mediate uPA-induced migration, and association of wt-uPAR to alpha3beta1 results in uPAR cleavage and extracellular signal-regulated kinase (ERK) activation. On the contrary, hcr-uPAR does not activate ERK and does not engage FPRL1 or any other G protein-coupled receptor, but it activates an alternative pathway initiated by the formation of a triple complex (uPAR-alpha3beta1-EGFR) and resulting in the autotyrosine phosphorylation of EGFR.
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PMID:An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration. 1626 71

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.
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PMID:uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues. 1709 Jun 87

The aim of this study is to investigate the anti-cancer effect of the bispecific diphtheria toxin (DT) based immunotoxin DTATEGF, which targets both the epidermal growth factor (EGF) receptor (EGFR) and the urokinase-type plasminogen activator (uPA) receptor (uPAR) in vitro and in vivo when delivered by convection-enhanced delivery (CED) via an osmotic minipump in a human metastatic non-small cell lung cancer (NSCLC) brain tumor mouse xenograft model. The effects of the bispecific immunotoxin DTATEGF, and monospecific DTAT, DTEGF and control DT at various concentrations were tested for their ability to inhibit the proliferation of human metastatic NSCLC PC9-BrM3 cells in vitro by MTT assay. A xenograft model of human metastatic NSCLC intracranial model was established in nude mice using the human NSCLC PC9-BrM3 cell line genetically marked with a firefly luciferase reporter gene. One microgram of DTATEGF in the treatment group or control DT in the control group was delivered intracranially by CED via an osmotic minipump. The bioluminescent imaging (BLI) was performed at day 7, 14, 1 month, 2 months, and 3 months. Kaplan-Meier survival curves for the two groups were generated. The brain tissue samples were stained by hematoxylin and eosin for histopathological assessment. In vitro, DTATEGF could selectively kill PC9-BrM3 cells and showed an IC(50) less than 0.001 nM, representing a more than 100- to 1000-fold increase in activity as compared to monospecific DTAT and DTEGF. In vivo, mice with tumors were treated intracranially with drug via CED where the results showed the treatment was successful in providing a survival benefit with the median survival of mice treated with DTATEGF being significantly prolonged relative to controls (87 vs. 63 days, P = 0.006). The results of these experiments indicate that DTATEGF kills the NSCLC PC9-BrM3 cell line in vitro, and when it is delivered via CED intracranially, it is highly efficacious against metastatic NSCLC brain tumors. DTATEGF is a safe and effective drug where further preclinical and clinical development is warranted for the management of metastatic brain tumors.
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PMID:Intracerebral infusion of the bispecific targeted toxin DTATEGF in a mouse xenograft model of a human metastatic non-small cell lung cancer. 2269 10

Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.
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PMID:Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A. 2846 15


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