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)

A case of endolymphatic stromal myosis (ELSM) with multiple metastasis to lungs was studied. A single biopsy specimen from the lung was analyzed for c-erbB-2, CD44E, and autocrine motility factor receptors (AMFR) mRNA expression, all putatively associated with metastasis. Estrogen and progestin receptors (ER, PR) expression were studied by reverse transcription polymerase chain reactions. Expression of an invasion-related gene, membrane type matrix metalloproteinase (MT-MMP) was also studied. The metastatic lesion showed positive expression of c-erbB-2, CD44E, AMFR, PR and ER expression, whereas no expression of MT-MMP was detected. These results correspond with the present clinical history that is early and multiple lung metastasis but essentially benign in nature and with excellent response to gestagen treatment.
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PMID:Pulmonary metastatic lesion of endolymphatic stromal myosis expresses metastasis-related genes but not invasion-related matrix type metalloproteinase. 906 35

Aberrant expression or activity of the epidermal growth factor (EGF) receptor family of tyrosine kinases has been associated with tumor progression and an invasive phenotype. In this study, we utilized 4 ovarian cancer cell lines, OVCA 432, DOV 13, OVEA6 and OVCA 429, to determine the effects of EGF on the regulation of proteolytic enzymes and their inhibitors, cellular migration and in vitro invasion. Induction of urinary-type plasminogen activator (u-PA) activity and tissue inhibitor of matrix metalloproteinase (TIMP)-1 was observed in all 4 cell lines. OVCA 432 cells showed strong PAI-1 induction; however, the other 3 lines displayed substantial baseline PAI-1 expression that was not induced by EGF. EGF-dependent stimulation of migration and induction of matrix metalloproteinase (MMP)-9 (gelatinase B) was observed in OVEA6 and OVCA 429 cells only. Upon EGF receptor activation, DOV 13, OVEA6 and OVCA 429 cells were induced to invade through an artificial basement membrane (Matrigel); however, no invasion was detected in OVCA 432 cells. Cell lines displaying induction of migration and MMP-9 (OVEA6 and OVCA 429) demonstrated robust EGF-induced invasion (5- to 20-fold), and cell invasion was substantially reduced in the presence of anti-catalytic MMP-9 antibody. Addition of anti-catalytic u-PA antibody inhibited the modest (<2-fold) EGF-induced invasion in a cell line that did not express MMP-9 (DOV 13) and in OVEA6 cells that displayed the highest baseline u-PA activity. Together, our findings indicate that multiple proteinases are important in ovarian cell invasion and implicate EGF induction of MMP-9 and migration as key components of more aggressive ligand-induced invasion.
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PMID:Proteinase requirements of epidermal growth factor-induced ovarian cancer cell invasion. 976 68

Pancreatic adenocarcinomas are among the most resistant neoplasms to conventional chemotherapeutics. This has prompted intense investigations of novel non-cytotoxic agents based on new understandings of the molecular pathobiology of human malignancies. This review will focus on the potential uses of three new classes of agents: farnesyl transferase (FTPase) inhibitors, matrix metalloproteinase inhibitors (MMPI's) and antibodies to the HER-2/neu oncogene. When used as single agents, FTPase inhibitors and MMPI's may be cytostatic, helping to delay the growth of these cancers. All three classes of agents may have the greatest benefit when used in conjunction with traditional anticancer modalities. The biology of these agents will reviewed.
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PMID:Novel approaches in development for the treatment of pancreatic cancer. 979 96

Overexpression of the crbB-2 gene-encoded p185(c-erbB-2) is correlated with early onset of metastasis in breast cancer patients. Furthermore, the detection of blood-borne epithelium-derived clustered cells expressing p185(c-erbB-2) was related to advanced stages in breast cancer. To further elucidate the receptor's function in the metastatic process of human breast cancers, we analyzed disaggregated cells and cell clusters from freshly dissected breast cancer tissues. We studied whether their capability of extravasation is correlated with their expression of c-erbB-2. A model for the venular wall was constructed by growing human umbilical vein endothelial cells (HUVECs) on porous membranes coated with basement membrane extracellular matrix. In four control breast cancer cell lines (SK-BR-3, MCF-7, MDA-MB-468, and MDA-MB-468, the latter transfected with a full-length c-erbB-2 cDNA vector) producing different levels of the c-erbB-2 receptor, the expression level correlated positively with the invasiveness of the cells. The invasive, predominantly clustered cells from 14 of 23 tumors were positively stained for p185(c-erbB-2) by immunocytochemistry. Furthermore, we show that the invasive cell populations express the metastasis-associated proteins matrix metalloproteinase MMP-2, CD44, and integrins alpha(v)beta3 and alpha6. In this first study on the behavior of cells and cell clusters from disaggregated operated cancers in an extravasation model, we could demonstrate the presence of c-erbB-2-expressing cell subpopulations within the individual breast cancers that are presumably of high metastatic potential.
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PMID:Selection of potentially metastatic subpopulations expressing c-erbB-2 from breast cancer tissue by use of an extravasation model. 984 70

Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as "state-of-the art" treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLCD-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials.
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PMID:Update on the management of advanced breast cancer. 1035 85

Breast cancer is the most common cancer and second leading cause of cancer related deaths in women in the United States. Genistein is a protein tyrosine kinase inhibitor and prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We have previously shown that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. In this study, we investigated these effects of genistein in the breast cancer cell line MDA-MB-435 and 435.eB cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. We also investigated the effect of genistein on matrix metalloproteinase (MMP) secretion previously shown to be effected by erbB-2 transfection. Genistein was found to inhibit MDA-MB-435 and 435.eB cell growth. Induction of apoptosis was also observed in these cell lines when treated with genistein, as measured by DNA laddering, poly(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. We also found an up-regulation of Bax and p21WAF1 expression and down-regulation of Bcl-2 and c-erbB-2 in genistein-treated cells. Gelatin zymography showed that genistein inhibits the secretion of MMP in the breast cancer cells. From these results, we conclude that genistein inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and may inhibit invasion and metastasis of breast cancer cells. These findings suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. 1042 35

Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and exhibits potent growth-inhibitory activity against a number of human tumor cell lines, both in vitro and when grown as xenografts in mice. It is presently being investigated as a novel antineoplastic agent in the primary screen conducted by the Developmental Therapeutics Program, National Cancer Institute. Because breast cancer is the most common cancer and second leading cause of cancer-related deaths in women in the United States, we investigated whether flavopiridol could be an effective agent against a series of isogenic breast- cancer cell lines having different levels of erbB-2 expression and differential invasion and metastatic characteristics. Flavopiridol was found to inhibit the growth of MDA-MB-435 (parental) and 435.eB (stable transfectants) cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. Induction of apoptosis was also observed in these cell lines when treated with flavopiridol, as measured by DNA laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax and down-regulation of Bcl-2, but there was a significant down-regulation of c-erbB-2 in flavopiridol-treated cells. Gelatin zymography showed that flavopiridol inhibits the secretion of matrix metalloproteinase (MMP; MMPs 2 and 9) in the breast cancer cells and that the inhibition of c-erbB-2 and MMPs may be responsible for the inhibition of cell invasion observed in flavopiridol-treated cells. Collectively, these molecular effects of flavopiridol, however, were found to be independent of c-erbB-2 overexpression, suggesting that flavopiridol may be effective in all breast cancer. From these results, we conclude that flavopiridol inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and inhibits invasion and, thus, may inhibit metastasis of breast cancer cells. These findings suggest that flavopiridol may be an effective chemotherapeutic or preventive agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. 1065 53

Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-beta1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-beta1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands.
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PMID:Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands. 1084 63

Ultraviolet (UV) irradiation causes human skin aging and skin cancer through the activation of matrix metalloproteinases (MMPs) which are responsible for the degradation of collagen and tumor progression in human skin. The molecular mechanisms of UV-induced MMPs are yet to be defined. Our previous studies and others suggest that i) the transient activation of cell surface receptors and subsequent activation of MAP kinase cascade contributes to the transcriptional up-regulation of MMPs; and ii) UV-induced expression of pro-inflammatory cytokines such as IL-1 beta and TNF-alpha may also account for the expression of MMPs. However, signaling pathway through which cytokines induce MMP expression remains to be unraveled. In this study, we investigated the pathway that leads to the IL-1 beta-induced up-regulation of MMP-1 in human keratinocytes. IL-1 beta activated epidermal growth factor (EGF) receptor in cultured human keratinocytes in a time- and dose-dependent manner. IL-1 beta-induced EGF receptor tyrosine phosphorylation started at 5 min and peaked at 10 min and remained elevated up to 40 min post IL-1 beta treatment. EGF receptor kinase inhibitor PD153035 and AG1478 inhibited IL-1 beta-induced EGF receptor tyrosine phosphorylation. To test the effect of EGF receptor transactivation on downstream components, we examined the ERK activation by IL-1 beta. We found that IL-1 beta-induced ERK phosphorylation, PD153035 and MEK inhibitor PD98059 blocked IL-1 beta-induced ERK activity. Furthermore, both inhibitors also dramatically reduced IL-1 beta-induced expression of c-jun and c-fos mRNA which are required for up-regulation of MMPs. EGF receptor kinase inhibitor PD153035 and AG1478 and MEK inhibitor PD98059 also blocked IL-1 beta induction of MMP-1 in cultured human keratinocytes. Collectively, our data indicate that IL-1 beta-induced expression of MMP-1 is mediated by transactivation of EGF receptor and through ERK pathway in human keratinocytes.
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PMID:Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes. 1117 16

Activation of the epidermal growth factor (EGF) receptor regulates many processes associated with metastasis, including modulation of cell:cell and cell:substrate interactions, production of matrix-degrading proteinases, and cellular migration. We have demonstrated previously that EGF stimulates migration and matrix metalloproteinase (MMP)-9-dependent invasion of ovarian cancer cells. In this study, we compare the roles of EGF-induced phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) activities in regulation of cellular responses associated with ovarian tumor cell metastasis. Inhibition of PI3K and MAPK activity impairs EGF-stimulated cell migration, in vitro invasion, and MMP-9 production. PI3K activity is not required for growth factor disruption of cell:cell junctions, whereas inhibitors of extracellular signal-regulated kinase (ERK)1/ERK2 activation and p38 MAPK activity block EGF-dependent junction dissolution. EGF promotes pro-MMP-9 binding to the cell surface through a mechanism that is independent of extracellular enzyme concentration. Interestingly, inhibition of PI3K activity abolishes EGF-induced cell surface association of pro-MMP-9, whereas inhibitors of MAPKs only partially block the response. These data suggest that EGF receptor activation promotes a PI3K-dependent induction of a cell surface pro-MMP-9 binding component that may facilitate gelatinase-mediated cellular invasion and supports an expanded role for elevated PI3K activity in cellular responses associated with ovarian tumor metastasis. In addition, our findings support the hypothesis that divergent kinase activities regulate distinct cellular events associated with growth factor-induced invasion of ovarian cancer cells.
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PMID:Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. 1128 Jul 38


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