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

Non-small cell lung cancer is the most common cause of cancer-related death in North America and Europe. Despite improvements in the diagnosis and treatment of the disease the prognosis remains poor, the overall 5-year survival being 4-14%. An increased understanding of the molecular biology of the disease may identify novel targets for drug development. We evaluated epidermal growth factor receptor (EGFR), HER-2/neu, matrix metalloproteinase (MMP)-2, MMP-9, p53 and bcl-2 expression and microvessel density (MVD) in patients who underwent surgery with curative intent in our department between 1991 and 1996. Co-expression of EGFR/MMP-9, MVD and bcl-2 were found to be independent prognostic variables, which allowed prediction of patient outcome independent of surgical stage. Other prognostic factors identified in our series were gender, surgical stage, platelet count, extent of necrosis, the hypoxia marker carbonic anhydrase-9 and beta-catenin. In collaboration with groups in Oxford and Greece, we were also able to establish the angiogenic growth factors vascular endothelial growth factor and platelet-derived endothelial growth factor as prognostic variables. The inter-relationships between these factors are currently being examined in an expanded patient series. Through this work we hope to be able to construct an integrated biological prognostic model which can be tested in prospective studies. This work has identified several potential targets for novel therapeutic agents currently in development.
 ...
PMID:Towards a biological staging model for operable non-small cell lung cancer. 1172 Jul 47

We attempted to investigate immunohistochemical expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PD-ECGF), c-erbB-2, matrix metalloproteinase-2 (MMP-2), and MMP-9 using surgical specimens of 119 non-small-cell lung carcinoma (NSCLC) cases and to evaluate the relationship between the expression levels of each molecule and clinicopathological factors or prognosis. VEGF expression levels were significantly associated with the local invasion (P = 0.0001), lymph node involvement (pN-factor) (P = 0.0019), pathological stage (p-stage) (P = 0.0027) and lymphatic permeation (P = 0.0389). PD-ECGF expression levels were associated with pN-factor (P = 0.0347). MMP-2 expression levels were associated with pN-factor (P = 0.004) and lymphatic permeation (P = 0.0056). Also, MMP-9 expression levels showed a significant correlation to local invasion (P = 0.0012), pN-factor (P = 0.0093) and p-stage (P = 0.0142). Multivariate analysis showed VEGF to be the most related to local invasion (P = 0.0084), and MMP-2 was the only factor with significant independent impact on lymphatic permeation (P = 0.0228). Furthermore, log-rank analysis showed significant association with poor survival by VEGF, bFGF, MMP-2 and MMP-9. Especially, combined overexpression of VEGF and MMP-2 revealed poor prognosis, our study might provide a basis for the better evaluation of biological characteristics and a new therapeutic strategy based on chemotherapy.
 ...
PMID:Influence of angiogenetic factors and matrix metalloproteinases upon tumour progression in non-small-cell lung cancer. 1174 92

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous regulators of matrix metalloproteinases (MMPs). They are believed to possess several distinct cellular functions, particularly the contradictory activities of inhibiting MMPs and promoting tumor cell growth. Immunohistochemistry was performed to detect TIMP-2 protein in 136 infiltrative breast carcinomas. TIMP-2 protein was analyzed in parallel with clinicopathologic features (tumor size, histologic type, nuclear and histologic grade, stage), patients' overall survival and ER, PR, Ki-67, topo IIalpha, c-erbB-2, p53 and bcl-2 proteins. Statistical analysis was performed using univariate and multivariate models analysis. Immunoreactivity for TIMP-2 was observed in cancer cells and stromal fibroblasts in 106 (77.94%) and 104 (76.47%) of 136 cases, respectively. TIMP-2 protein expression in stromal fibroblasts showed a statistically significant inverse correlation with tumor size (P =.014). An inverse correlation was also observed between TIMP-2 epithelial immunoreactivity and nuclear and histologic grade (P =.036 and P =.007, respectively). TIMP-2 protein reactivity showed statistically significant positive associations with topo IIalpha and bcl-2 in stromal and cancer cells, respectively (P =.032 and P =.001, respectively). TIMP-2 protein expression in cancer and stromal cells was associated with better patients' overall survival (P =.002 and P =.038, respectively). When evaluated by the Cox's proportional hazard regression model, this association was further established, but only as far as TIMP-2 expression in tumor epithelium was concerned (P =.019). Our results support the multifunctional potential of TIMP-2 through its correlation on the one hand to a favorable outcome, due to its MMP inhibitory activity and on the other to topo IIalpha contributing to its growth factor activity.
 ...
PMID:Correlation of tissue inhibitor of metalloproteinase-2 with proliferative activity and patients' survival in breast cancer. 1179 38

Angiotensin II (Ang II) may cause cardiac hypertrophy via type 1 Ang II receptors (AT(1)) on cardiomyocytes and through growth factors released from cardiac fibroblasts. Whereas cardiomyocyte-specific AT(1) receptor expression produces cardiac hypertrophy and remodeling in vivo, delineation of the signals that mediate growth to Ang II is challenging because the prevailing in vitro model (cultured neonatal cardiomyocytes) expresses low levels of AT(1) receptor and responds inconsistently to Ang II. In this study, when AT(1A) receptors were expressed using adenovirus in cultured neonatal cardiomyocytes, Ang II stimulated a robust hypertrophy that was not secondary to the release of cardiac fibroblast-derived factors, specifically endothelin-1. Hypertrophy was accompanied by the induction of the immediate-early response genes, c-fos and c-jun, and reexpression of atrial natriuretic peptide (ANP). Ang II-induced activation of an ANP promoter-reporter was inhibited by the dominant/negative mutants, GalphaqI and N17Ras, indicating that hypertrophic signaling by the AT(1A) receptor is via heterotrimeric G protein coupling and downstream Ras pathways. AT(1A)-mediated cardiomyocyte hypertrophy and mitogen-activated protein kinase (MAPK) activation were inhibited by the MAPK kinase inhibitor, PD98059, and the epidermal growth factor (EGF) receptor kinase antagonist, AG1478, but not by PKC inhibitor, bisindolylmaleimide-1. Moreover, Ang II-induced MAPK activation was prevented by treatment with a matrix metalloproteinase inhibitor, consistent with the tyrosine phosphorylation of the EGF receptor in response to AT(1A) receptor activation. These data unequivocally demonstrate that Ang II can directly promote cardiac myocyte growth via AT(1A) receptors expressed on these cells and reveal for the first time the important contribution of EGF receptor-transactivated MAPK signaling to this process.
 ...
PMID:Adenoviral-directed expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via transactivation of the epidermal growth factor receptor. 1183 5

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
 ...
PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of proinflammatory cytokines from colonic epithelial cells. SP also stimulates cell proliferation, a critical event in tissue healing during chronic colitis, via transactivation of the epidermal growth factor (EGF) receptor (EGFR) and activation of mitogen-activated protein kinase (MAPK). Here we examined the mechanism by which SP induces EGFR and MAPK activation. We used non-transformed human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) as well as untransfected U373 MG cells expressing high levels of endogenous NK-1R. Exposure of both cell lines to SP (10(-7) m) stimulated EGFR activation (1 min) followed by extracellular signal-regulated protein kinase (ERK1/2) activation (2-5 min). SP-induced ERK1/2 activation was blocked by pretreatment with the metalloproteinase inhibitor Batimastat/GM6001, the EGFR phosphorylation inhibitor AG1478, and the tumor necrosis factor-alpha-converting enzyme (TACE) inhibitor TAPI-1. Pretreatment with antibodies against potential EGFR ligands suggested that transforming growth factor-alpha (TGFalpha), but not the other EGFR ligands EGF, heparin-binding EGF, or amphiregulin, mediates SP-induced EGFR transactivation. SP stimulated TGFalpha release into the extracellular space that was measurable within 2 min, and this release was inhibited by metalloproteinase inhibitors and the TACE inhibitor TAPI-1. SP also induced MAPK-mediated cell proliferation that was inhibited by TACE, matrix metalloproteinase (MMP), EGFR, and MEK1 inhibitors. Thus, in human colonocytes, NK-1R-induced EGFR and MAPK activation and cell proliferation involve matrix metalloproteinases (most likely TACE) and the release of TGFalpha. These signaling mechanisms may be involved in the protective effects of NK-1R in chronic colitis.
 ...
PMID:Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes. 1531 41

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.
 ...
PMID:[Effect of genistein on expression of angiogenesis related factors in HER-2/neu-overexpressing breast cancer cells]. 1532 30

The dermatotoxicity of arsenic is well established and epidemiological studies identify an increased incidence of keratinocytic tumors (basal cell and squamous cell carcinoma) associated with arsenic exposure. Little is known about the underlying mechanisms of arsenic-mediated skin carcinogenesis, but activation of mitogen-activated protein (MAP) kinases and subsequent regulation of downstream target genes may contribute to tumor promotion and progression. In this study, we investigated activation of the extracellular signal regulated kinase (ERK) and the stress-associated kinase p38 by arsenite in HaCat cells, a spontaneously immortalized human keratinocyte cell line. Arsenite concentrations > or =100 microM stimulate rapid activation of p38 and ERK MAP kinases. However, upon extended exposure (24 h), persistent stimulation of p38 and ERK MAP kinases was detected at low micromolar concentrations of arsenite. Although ERK and p38 were activated with similar time and concentration dependence, the mechanism of activation differed for these two MAP kinases. ERK activation by arsenite was fully dependent on the catalytic activity of the epidermal growth factor (EGF) receptor and partially dependent on Src-family kinase activity. In contrast, p38 activation was independent of EGF receptor or Src-family kinase activity. Arsenite-stimulated MAP kinase signal transduction resulted in increased production of matrix metalloproteinase (MMP)-9, an AP-1 regulated gene product. MMP-9 induction by arsenite was prevented when EGF receptor or MAP kinase signaling was inhibited. These studies indicate that EGF receptor activation is a component of arsenite-mediated signal transduction and gene expression in keratinocytes and that low micromolar concentrations of arsenite stimulate key signaling pathways upon extended exposure. Stimulation of MAP kinase cascades by arsenic and subsequent regulation of genes including c-fos, c-jun, and the matrix degrading proteases may play an important role in arsenic-induced skin carcinogenesis.
 ...
PMID:Roles of mitogen activated protein kinases and EGF receptor in arsenite-stimulated matrix metalloproteinase-9 production. 1550 54

Mild doses of oxidative stress in the heart correlate with the induction of apoptosis or hypertrophy in cardiomyocytes (CMCs) and fibrosis or proliferation of fibroblasts. Three branches of mitogen-activated protein kinases (MAPKs), i.e., c-Jun N-terminal kinases (JNKs), extracellular signal-related kinases 1 and 2 (ERK1/2), and p38, are activated by oxidants in a variety of cell types, including CMCs. However, the initiation process of these signaling pathways remains unsolved. We explored the role of the epidermal growth factor (EGF) receptor in H(2)O(2)-induced MAPK activation using two different cell types from the same organ: CMCs and heart fibroblasts (HFs). Pretreatment of each cell type with EGF revealed differences in how CMCs and HFs responded to subsequent treatment with H(2)O(2): in CMCs, the second treatment resulted in little further activation of JNKs and ERK1/2, whereas HFs retained the full response of JNKs and ERK1/2 activation by H(2)O(2) regardless of EGF pretreatment. AG-1478 [4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline], a pharmacologic inhibitor of the EGF receptor tyrosine kinase, inhibited JNK and ERK1/2 activations but not p38 in both cell types. The data using the Src inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] resemble those found when using AG-1478 in either cell type. Pharmacologic inhibitors of matrix metalloproteinases (MMPs) further illustrated the difference between the two cell types. In HFs, MMP inhibitors GM6001 [N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide] and BB2516 [[2S-[N4(R(*)),2R(*),3S(*)]]-N4-[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3-(2-methylpropyl)butanediamide, marimastat] inhibited JNKs and ERK1/2 activation without affecting p38 activation by H(2)O(2) inhibitors. In contrast, these MMP failed to significantly inhibit the activation of JNKs, ERKs, or p38 in CMCs. These data suggest the complexity of the cell type-dependent signaling web initiated by oxidants in the heart.
 ...
PMID:Epidermal growth factor receptor-dependent and -independent pathways in hydrogen peroxide-induced mitogen-activated protein kinase activation in cardiomyocytes and heart fibroblasts. 1557 83

The ligand-less receptor HER2/neu (erbB-2) has been proposed as a prognostic marker of gastric cancer that correlates with poor clinical outcome, indicating that HER2 signals play an important role in gastric cancer progression. This study demonstrated that two major natural lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), induce rapid and transient phosphorylation of HER2 in two human gastric cancer cell lines, MKN28 and MKN74 cells. We also revealed that tyrosine phosphorylation of HER2 induced by both lysophospholipids was significantly attenuated by two inhibitors, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This suggests that the pathway of HER2 transactivation induced by these lysophospholipids is dependent on the proteolytically released EGFR ligands. Our results indicate that LPA and S1P act upstream of HER2 in gastric cancer cells, and thus may act as potent stimulators of gastric cancer.
 ...
PMID:Lysophospholipids transactivate HER2/neu (erbB-2) in human gastric cancer cells. 1564 31


<< Previous 1 2 3 4 Next >>