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)

Previous studies have implicated ADP-ribosylation in the mechanism of TNF cytotoxicity. In short-term 51Cr-release assays with several mouse and human tumor cell lines, the inhibitors aminobenzamide (ABA) and nicotinamide (NA) of ADP-ribosylation sensitized HER-2/neu-nonoverexpressing cells (CaOV-3 and MCF-7) but not HER-2/neu-overexpressing cells (SKOV-3 and SKBR-3) to TNF. However, both inhibitors alone or in combination with either TNF and/or actinomycin D (AD) caused similar effects on ADP-ribosylation rates of CaOV-3 and SKOV-3 cells after 4 h of treatment. This result suggests that ADP-ribosylation may not be involved in sensitizing these human tumor cells to TNF. Both ABA and NA decreased the TNF sensitivity of L929 cells and either increased or decreased TNF sensitivity of EMT-6 cells in the absence or presence of actinomycin D, respectively. Again, there was no correlation between ADP-ribosylation and TNF cytotoxicity in these mouse cell lines. Thus, modulation of TNF sensitivity by these inhibitors might be linked to a compromised repair mechanism distinct from the effects on ADP-ribosylation alone.
Lymphokine Cytokine Res 1994 Apr
PMID:TNF cytotoxicity: effects of HER-2/neu expression and inhibitors of ADP-ribosylation. 791 50

HER-2/neu peptides have recently been shown to induce a proliferative response by peripheral CD4(+) T cells in breast cancer patients. To investigate potential differences in the local cellular immune response between breast cancer patients with and without nodal metastases, lymphocytes were isolated from axillary lymph nodes from patients with breast cancer, and proliferative and cytokine responses to HER-2/neu peptides were determined. Freshly isolated lymphocytes from lymph nodes of 7 women undergoing surgery for invasive breast cancer were plated at 20 x 10(5) cells per well in triplicate. Cells were stimulated with HER-2/neu peptides at 50 microg/ml and with control antigens. Incorporation of tritium-labeled thymidine was determined 4 days later. The levels of the cytokines interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and IL-10 were determined at priming and at restimulation with HER-2/neu peptides using a cytokine-specific, double-sandwich, enzyme-linked immunosorbent assay (ELISA). Lymphocytes isolated from the axillary lymph nodes of the patients mounted significant cellular immune response to HER-2/neu peptides, manifested by proliferation and specific cytokine elaboration. Proliferative responses to HER-2/neu peptides were seen in lymphocytes of patients with and without overexpression of HER-2/neu in the primary tumor. In some patients, the proliferative response to HER-2/neu peptides in lymphocytes from lymph nodes with metastases was absent or blunted compared with the response in lymphocytes from lymph nodes without metastases from the same patient (p < 0.05). HER-2/neu peptides induced a predominantly T helper type 1 (Th1) pattern of cytokine response in nodal lymphocytes isolated from breast cancer patients. A Th1-specific cytokine production pattern was maintained at priming and restimulation with HER-2/neu peptides and was amplified with IL-12 costimulation. These results indicate that HER-2/neu peptides can activate T cells in draining lymph nodes from women with invasive breast cancer. This activation is associated with a predominantly Th1 cytokine response, which suggests that conditioning with HER-2/neu peptides may be of value in the development of breast cancer vaccines.
J Interferon Cytokine Res 2002 May
PMID:Axillary lymph node cellular immune response to HER-2/neu peptides in patients with carcinoma of the breast. 1206 Apr 97

The pathogenesis of allergic asthma involves the interplay of inflammatory cells and airway-resident cells, and of their secreted mediators including cytokines, chemokines, growth factors and inflammatory mediators. Receptor tyrosine kinases are important for the pathogenesis of airway remodeling. Activation of epidermal growth factor (EGF) receptor kinase and platelet-derived growth factor (PDGF) receptor kinase leads to hyperplasia of airway smooth muscle cells, epithelial cells and goblet cells. Stimulation of non-receptor tyrosine kinases (e.g. Lyn, Lck, Syk, ZAP-70, Fyn, Btk, Itk) is the earliest detectable signaling response upon antigen-induced immunoreceptor activation in inflammatory cells. Cytokine receptor dimerization upon ligand stimulation induces activation of Janus tyrosine kinases (JAKs), leading to recruitment and phosphorylation of signal transducer and activator of transcription (STAT) for selective gene expression regulation. Activation of chemokine receptors can trigger JAK-STAT pathway, Lck, Fyn, Lyn, Fgr, and Syk/Zap-70 to induce chemotaxis of inflammatory cells. Inhibitors of tyrosine kinases have been shown in vitro to block growth factor-induced hyperplasia of airway-resident cells; antigen-induced inflammatory cell activation and cytokine synthesis; cytokine-mediated pro-inflammatory gene expression in inflammatory and airway cells; and chemokine-induced chemotaxis of inflammatory cells. Recently, anti-inflammatory effects of tyrosine kinase inhibitors (e.g. genistein, tyrphostin AG213, piceatannol, tyrphostin AG490, WHI-P97, WHI-P131, Syk antisense) in animal models of allergic asthma have been reported. Therefore, development of inhibitors of tyrosine kinases can be a very attractive strategy for the treatment of asthma.
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PMID:Tyrosine kinase inhibitors: a new approach for asthma. 1502 50

Identification of genes/proteins that are differentially expressed in HER2 (erbB-2) oncogene-dependent breast carcinomas is essential in elucidating the mechanistic basis of their increased metastastic potential and resistance to several anti-cancer therapies. We here applied human cytokine antibody arrays with the goal of identifying a unique HER2-induced 'cytokine signature' in breast cancer. Human Cytokine Array III (RayBiotech, Inc.), which simultaneously detects 42 cytokines and growth factors on one membrane, was used to determine the profile of cytokines in conditioned media obtained from MCF-7/Her2-18 cells, a MCF-7-derived clone engineered to stably express the full-length human HER2 cDNA controlled by a SV40 viral promoter, and from the MCF-7/neo control sub-line. We identified two inflammatory and pro-angiogenic CXC chemokines with at least a 10-fold increased expression in HER2-overexpressing MCF-7/Her2-18 transfectants when compared to matched control MCF-7/neo cells: CXCL8 (IL-8; Interleukin-8) and CXCL1 and (GRO; Growth-related oncogene). HER2-induced differential overexpression of IL-8 and GRO was validated by ELISA and further confirmed by switching off the HER2 signalling. Treatment with the tyrosine kinase inhibitor gefitinib (Iressa) returned the expression levels of IL-8 and GRO back to the baseline observed in MCF-7 breast cancer cells, which express physiological levels of HER2. To evaluate the diagnostic utility of these findings, cytokine-specific antibody arrays were incubated with sera retrospectively collected from metastatic breast cancer patients. This approach revealed a high similarity between the 'cytokine signature' observed in serum samples and that obtained in media conditioned by breast cancer-derived cell lines. Thus, IL-8 and GRO circulating levels were significantly higher in HER2-positive breast cancer patients compared with HER2-negative patients. These findings reveal for the first time that: a) Enhanced synthesis and secretion of members of the IL-8/GRO chemokine family, which have recently been linked to oestrogen receptor (ER) inaction, increased cell invasion and angiogenesis, may represent a new pathway involved in the metastatic progression and endocrine resistance of HER2-overexpressing breast carcinomas, and b) Circulating levels of IL-8 and GRO cytokines may represent novel biomarkers monitoring breast cancer responses to endocrine treatments and/or HER2-targeted therapies.
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PMID:Protein array technology to detect HER2 (erbB-2)-induced 'cytokine signature' in breast cancer. 1737 3