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)

The response of malignant and nonmalignant human breast cell lines to the growth inhibitory effects of monoclonal antibodies against the epidermal growth factor (EGF) receptor was studied. A series of human breast cell lines, which express EGF receptor, were used: MDA-468, MDA-231, and Hs578T human breast cancer cells and the transformed human mammary epithelial cell lines 184A1N4 and 184A1N4-T that have been benzo[a]pyrene immortalized and further transformed with SV40T, respectively. Four antibodies of two different classes were tested: 225 immunoglobulin G (IgG), 108.4 IgG, 96 immunoglobulin M (IgM), and 42 IgM. All four antibodies inhibited the anchorage-dependent and -independent, EGF-stimulated growth of 184A1N4 and 184A1N4-T cells, respectively, and this growth inhibition could be reversed by the addition of increasing concentrations of EGF. In contrast, the antibodies inhibited the anchorage-dependent and -independent growth of MDA-468 cells in the absence of exogenous EGF suggesting that the antibodies were acting to block access of an endogenously produced ligand to the EGF receptor. In the presence of antibody and increasing concentrations of EGF, MDA-468 cell growth was first stimulated then inhibited as the EGF concentration increased, thus, uncovering the growth stimulatory potential of low concentrations of EGF in these cells. Data is presented that indicates MDA-468 cells secrete a transforming growth factor with autocrine growth stimulatory capabilities. The growth of MDA-231 and Hs578T cells, which contain activated ras oncogenes, was not inhibited by the antibodies and the growth of these cell lines was not stimulated by EGF. Of the cell lines studied only MDA-468 cells appear to possess an autocrine growth stimulatory capacity.
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PMID:Anti-epidermal growth factor receptor antibodies inhibit the autocrine-stimulated growth of MDA-468 human breast cancer cells. 260 59

We have investigated the actions of transforming growth factor (TGF) type alpha on epidermal growth factor (EGF) receptor mRNA expression in MDA-468 human mammary carcinoma cells in serum-free media. We found that exposure of MDA-468 cells to TGF alpha results in elevated levels of EGF receptor mRNA. This increase in mRNA accumulation showed time and dose dependence. Addition of TGF beta 1 enhanced the accumulation of EGF receptor mRNA induced by TGF alpha in a time- and dose-dependent manner. We also found that triiodothyronine at physiological concentrations exerts synergistic control on the action of TGF alpha alone, or in association with TGF beta 1, on EGF receptor mRNA expression. Similarly, retinoic acid treatment also enhanced in a time- and dose-dependent manner the TGF alpha-dependent response of EGF receptor mRNA and acted synergistically with TGF beta 1. The results described here suggest that optimum regulation of EGF receptor gene expression by TGF alpha is a complex process involving synergistic interactions with heterologous growth factors and hormones.
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PMID:Modulation of transforming growth factor alpha-dependent expression of epidermal growth factor receptor gene by transforming growth factor beta, triiodothyronine, and retinoic acid. 261 50

The mouse monoclonal antibody (mAb) 225 IgG1 against the epidermal growth factor (EGF) receptor has been investigated for its capacity to localize in human tumor xenografts. The EGF receptor is the product of the c-erb-B proto-oncogene (also known as EGFR). Elevated expression of EGF receptors has been demonstrated in many human tumors and tumor cell lines. We studied A431 human vulvar squamous cell carcinoma cells, with 2 X 10(6) receptors per cell; MDA-MB-468 (MDA 468) human breast adenocarcinoma cells, with 3 X 10(5) receptors per cell; and MCF-7 human breast adenocarcinoma cells, with 5 X 10(3) receptors per cell. The 111In-labeled pentetic acid (DTPA), derivative of mAb 225 (111In-DTPA-225) was injected intraperitoneally into nude mice bearing subcutaneous tumor xenografts. We measured uptake by quantifying radioactivity in tumor and normal tissues and by obtaining gamma camera images. Uptake in A431 xenografts was 28% +/- 2.4% of the injected dose per gram of tumor on day 3 and 12.4% +/- 3.0% on day 7. Distribution ratios comparing uptake in the tumor with that in normal tissues were consistently greater than 4. In contrast, there was far less uptake of the control mAb KS1/4S-1 labeled with 111In. This conjugate, 111In-DTPA-KS1/4S-1, has an IgG1 isotype but does not bind to human or murine cells. Imaging of the tumor with mAb 225 was excellent, especially on days 3-7. MDA 468 xenografts exhibited reduced localization of mAb 225 in the tumor. For MCF-7 xenografts, the tumor uptake of mAb 225 after 7 days was only 0.70% +/- 0.10% of the injected dose per gram of tumor, which was comparable to the uptake of the KS1/4S-1 control mAb. The ratio of the concentration of radioactivity in the tumor to that in normal tissue (distribution ratio) showed poor selectivity of uptake, and imaging was not obtained. These observations suggest that labeled mAb can target the product of a proto-oncogene, the EGF receptor, when it is expressed at high levels in human tumor xenografts.
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PMID:Imaging of human tumor xenografts with an indium-111-labeled anti-epidermal growth factor receptor monoclonal antibody. 279 90

The epidermal growth factor receptor (EGF-R) and the erbB-2 proto-oncogene product protein are closely related by their structural homology and their shared enzymatic activity as autophosphorylating tyrosine kinases. We show that in mammary tumor cells (SK-BR-3) EGF causes a rapid increase in tyrosine phosphorylation of the erbB-2 protein. Phosphorylation of erbB-2 does not occur in cells lacking the EGF-R (MDA-MB-453). Phosphorylation of erbB-2 in SK-BR-3 cells is blocked if EGF is prevented from interacting with its receptor by specific monoclonal antibodies. While EGF induces the down-regulation of its receptor in SK-BR-3 cells, EGF has no effect on the stability of the erbB-2 protein. This result suggests that the erbB-2 protein is a substrate of the EGF-R and indicates the possibility of communication between these two proteins early in the signal transduction process.
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PMID:Egf binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3. 290 52

The MDA 468 human breast carcinoma cell line was examined for changes in epidermal growth factor (EGF) receptor synthesis and degradation under the influence of EGF. This cell line was used because it overexpresses the EGF receptor such that each cell has 10(6) receptors, but unlike the well-studied A431 cell, its receptor gene is amplified but is not rearranged. On exposure to EGF, total cellular receptor protein, measured by immunoprecipitation with monoclonal antibody B1D8, is reduced. The half-life of receptor metabolically labeled with L-[35S]methionine is 24 h in the absence of EGF and is reduced to 12 h in the presence of 10(-9) M EGF. To measure the effect of EGF on synthesis of the receptor, pulse labeling conditions were selected in which the rate of synthesis of the receptor precursor were followed. EGF had no significant effect on the rate of general protein synthesis in these cells, yet stimulated the synthesis of the EGF receptor 1.8-fold over the unstimulated rate. This increase in receptor precursor synthesis showed time and dose dependence. Stimulation could be detected after 3 h exposure to EGF with a maximum at 6-8 h. A concentration of 10(-11) M EGF gave detectable stimulation with maximal stimulation occurring at 10(-9) M. Longer times and higher concentrations gave submaximal stimulation. A similar dose-response relationship was observed when the rate of mature 170-kDa receptor protein synthesis was measured. These studies demonstrate that EGF stimulates the synthesis of it own receptor. Downregulation of the receptor by EGF results from an increased rate of receptor degradation and not decreased synthesis.
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PMID:Epidermal growth factor stimulates the synthesis of its own receptor in a human breast cancer cell line. 300 20

The effects of the tumor promoter phorbol 12-tetradecanoate 13-acetate (TPA) on the epidermal growth factor (EGF) receptor levels were investigated in hormone-dependent (MCF-7, T-47-D, and ZR-75-1) and hormone-independent (MDA-MB-231, HBL-100, and BT-20) human mammary carcinoma cell lines. In the absence of TPA, hormone-independent cell lines contained high concentrations of low-affinity EGF receptors (apparent Kd = 8 X 10(-10) M), whereas hormone-dependent cell lines exhibited low concentrations of high-affinity receptors (apparent Kd = 1 X 10(-10) M). TPA causes a change of the receptor from a high- to the low-affinity state in hormone-dependent cell lines (MCF-7, T-47-D, and ZR-75-1), as well as in the hormone-independent HBL-100, whereas the affinity remained unchanged in MDA-MB-231 and BT-20 cells. In addition, progesterone receptor levels are decreased after TPA treatment in the hormone-dependent cell lines MCF-7, T-47-D, and ZR-75-1, whereas the estrogen receptor levels remained unchanged. Tumor promoters such as TPA or teleocidin inhibited the proliferation of these cell lines at concentrations above 10 microM with the exception of the T-47-D cells. The most sensitive cell line towards growth inhibition by tumor promoter was the hormone-dependent MCF-7 cell line. Evaluation of different TPA analogs indicated a positive correlation between the growth-inhibitory effects and their ability to stimulate the subcellular redistribution of protein kinase C activity in MCF-7 cells. These data suggest a protein kinase C-mediated down-regulation of the progesterone receptor concentration and of the EGF receptor affinity, which is supposed to mediate the mitogenic response. Furthermore, these results support the hypothesis that the tumor-derived growth factors induced by estradiol act via the EGF receptor in hormone-dependent mammary carcinoma cells.
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PMID:Correlation between hormone dependency and the regulation of epidermal growth factor receptor by tumor promoters in human mammary carcinoma cells. 300 36

Metabolism of the epidermal growth factor (EGF) receptor was studied in the MDA-MB-231 human breast cancer cell line. As in normal fibroblasts the EGF receptor from MDA-MB-231 cells was synthesized from a Mr = 160,000 precursor and tunicamycin treatment of cells resulted in accumulation of a Mr = 130,000 polypeptide. Unlike normal fibroblasts in which a Mr = 170,000 mature form of the EGF receptor was found, MDA-MB-231 cells contained a Mr = 172,000 mature form. Addition of EGF to MDA-MB-231 cells led to rapid internalization of EGF receptors, however, internalization did not affect receptor half-life and receptors did not recycle to the cell surface. EGF receptors could be visualized by immunofluorescence and remained sequestered in intracellular membranous structures following internalization. EGF was degraded slowly by MDA-MB-231 cells relative to degradation of EGF by normal cells. A high endogenous level of in vivo phosphorylation of threonine 654 of the EGF receptor was found in MDA-MB-231 cells and treatment of cells with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) further stimulated phosphorylation of this residue. EGF induced receptor internalization resulted in dephosphorylation of threonine 654. The significance of these unusual properties of EGF receptor metabolism in MDA-MB-231 cells is discussed.
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PMID:Epidermal growth factor induces internalization but not degradation of the epidermal growth factor receptor in a human breast cancer cell line. 305 91

The MDA-468 human breast cancer cell line has an amplified epidermal growth factor (EGF) receptor gene (20 x) and correspondingly overexpresses the EGF receptor. Since this cell line is growth inhibited by supra-physiological levels of EGF in tissue culture, it has been possible to select variant cells which have lost the chromosome bearing the amplified EGF receptor domain and which are capable of growing in high levels of EGF. One such cell line (MDA-468-S4) shows an absolute requirement for EGF for growth in anchorage-independent tissue culture conditions. We have utilized MDA-468 and MDA-468-S4 to examine the intracellular transduction of EGF signals leading to growth inhibition and proliferation, respectively. We report that in anchorage-independent conditions, pertussis toxin can abrogate both the EGF-dependent growth inhibition in MDA-468 cells and the EGF-dependent cell proliferation in MDA-468-S4 cells. This inhibition is paralleled by the ADP-ribosylation of an endogenous 41,000-dalton membrane protein in both MDA-468 and MDA-468-S4 cells. In contrast, the toxin does not prevent the transient, augmented expression of c-myc and c-fos mRNA seen in response to EGF in both cell types. These data suggest 1) the notion of more than one simultaneous, parallel, intracellular EGF-dependent signal transduction pathway and 2) G-protein involvement in at least one pathway mandatory for the growth modulating responses to EGF in anchorage-independent conditions, but distinct from that inducing c-myc and c-fos mRNA expression.
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PMID:G-protein-mediated epidermal growth factor signal transduction in a human breast cancer cell line. Evidence for two intracellular pathways distinguishable by pertussis toxin. 312 85

Modulation of epidermal growth factor (EGF) receptor expression determines cellular responsiveness to EGF and might play an important role in growth inhibition. We have investigated the actions of EGF and/or transforming growth factor type beta (TGF beta) on EGF receptor gene expression in MDA-468 human breast carcinoma cell line, which responds to EGF and/or TGF beta with growth inhibition. Using the cDNA clone pE7, which encodes 2.4 kilobases of the human EGF receptor mRNA, as a hybridization probe, we have found that exposure of MDA-468 cells to EGF results in elevated levels of EGF receptor mRNA. This increase in mRNA accumulation showed time and dose dependence. Addition of TGF beta enhances the accumulation of EGF receptor mRNA induced by EGF. Under this condition, stimulation could be detected after 1 h exposure to TGF beta with a maximum at 6-8 h. A concentration of 10 pM TGF beta gave detectable stimulation with maximal stimulation occurring at 300 pM in the presence of EGF (50 ng/ml). In contrast, TGF beta alone had no significant effect on EGF receptor mRNA accumulation. In the presence of cycloheximide, the EGF receptor mRNA was super-induced in response to EGF. Treatment of the cells with TGF beta enhances the EGF-dependent superinduction of EGF receptor mRNA produced by cycloheximide, suggesting that the stimulatory action of TGF beta does not depend on continuous protein synthesis. The results described here are consistent with the hypothesis that the growth inhibitory action of TGF beta in MDA-468 cells may be mediated, at least in part, by modulation of EGF receptor gene expression.
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PMID:Modulation of epidermal growth factor receptor gene expression by transforming growth factor-beta in a human breast carcinoma cell line. 349 59

Expression of epidermal growth factor (EGF) receptor by human breast cancer tissues has an inverse relationship with expression of the estrogen receptor and may be associated with a poor clinical response. We have studied the regulation of EGF receptor expression in a series of human breast cancer cell lines with varying degrees of estrogen responsiveness. Three estrogen receptor-positive lines, MCF-7, ZR-75-1, and T47D, were found to have less than 70,000 EGF binding sites per cell by radioreceptor assay and were growth stimulated in vitro by EGF. Four estrogen receptor-negative lines, MDA-MB-231, Hs578T, EVSA-T, and BT-20, contained greater than 70,000 EGF binding sites per cell and showed no in vitro growth stimulation by EGF. In all cell lines EGF receptor number was correlated with the amount of EGF receptor protein and RNA. Differences in EGF receptor expression between the cell types was not due to amplification of the EGF receptor gene. Rather, variations in EGF receptor expression between lines were due, at least in part, to differences in the rate of EGF gene transcription as determined by nuclear run-off studies. Our data confirm the previously described inverse relationship between expression of EGF and estrogen receptors. We show here that the absence of estrogen receptor expression in human breast cancer cell lines is associated with higher levels of functional EGF receptor protein and mRNA.
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PMID:Epidermal growth factor receptor gene expression in estrogen receptor-positive and negative human breast cancer cell lines. 350 7


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