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)

Adenoviruses are currently widely used as vectors in gene therapy. The steps involved in adenoviral infection have been investigated, but the factors regulating viral entry to the cell have not been clearly identified. We observed a high adenoviral infection rate in HER-2/neu-overexpressing breast cancer cells in vitro (435.eb1 and MCF-7/H18) and in vivo (435.eb1). We used emodin, a tyrosine kinase inhibitor that suppresses autophosphorylation and transphosphorylation activities of the HER-2/neu tyrosine kinase, to test the role of HER-2/neu in adenoviral transduction. Emodin treatment resulted in a marked decrease in the transduction efficiency of HER-2/neu-overexpressing cells but not in the parental cells. Because previous studies have shown that epidermal growth factor and tumor growth factor-alpha increase the expression level of integrin. Because integrin alphav is known as a promotor of viral internalization, penetration, or both, we investigated whether the observed increased transduction rate in HER-2/neu transfectants was mediated through the increased expression of integrin alphav. To test this hypothesis, we examined the level of integrin alphav of in HER-2/neu overexpressing cells. We found that the level of integrin alphav expression detected in HER-2/neu overexpressing cells by immunoblot analysis was similar to the level of integrin alphav found in its parental cells. These results suggest that HER-2/neu expression may have a significant role in the viral transduction efficiency through an integrin alphav independent pathway.
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PMID:Enhanced adenoviral transduction efficiency in HER-2/neu-overexpressing human breast cancer cells not induced by an integrin pathway. 1052 88

We present an approach for evaluating the efficacy of combination antitumor agent schedules that accounts for order and timing of drug administration. Our model-based approach compares in vivo tumor volume data over a time course and offers a quantitative definition for additivity of drug effects, relative to which synergism and antagonism are interpreted. We begin by fitting data from individual mice receiving at most one drug to a differential equation tumor growth/drug effect model and combine individual parameter estimates to obtain population statistics. Using two null hypotheses: (i) combination therapy is consistent with additivity or (ii) combination therapy is equivalent to treating with the more effective single agent alone, we compute predicted tumor growth trajectories and their distribution for combination treated animals. We illustrate this approach by comparing entire observed and expected tumor volume trajectories for a data set in which HER-2/neu-overexpressing MCF-7 human breast cancer xenografts are treated with a humanized, anti-HER-2 monoclonal antibody (rhuMAb HER-2), doxorubicin, or one of five proposed combination therapy schedules.
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PMID:A model-based approach for assessing in vivo combination therapy interactions. 1055 66

Blood lymphocytes of a HLA-A2 positive breast cancer patient were stimulated with either MCF-7 or MDA-MB-231, i.e., HLA-A2-matched allogeneic breast carcinoma cell lines. Several CD8+ CTL clones with reactivity against the stimulator cells but not against K562 were generated. Reactivity could be blocked with monoclonal antibody (mAb) W6/32, MA2.1, and/or BB7.2, indicating that the clones are HLA-class I and HLA-A2 restricted. The CTL clones generated following stimulation with MCF-7, recognized various other allogeneic HLA-A2+ tumor cell lines, including breast carcinoma, renal cell carcinoma, and melanoma cell lines, but not HLA-A2 tumor cell lines. The CTL clones did not recognize normal HLA-A2+ cells including breast epithelial cells, renal proximal tubular epithelial cells (PTEC), or EBV-transformed B cells including the autologous EBV cell line. In contrast to the CTL clones induced with MCF-7, the reactivity of the clones stimulated with MDA-MB-231, was limited to the stimulator cell MDA-MB-231. Cytotoxicity assays utilizing T2 cells loaded with peptides as target cells indicated that none of the examined CTL-epitopes derived from HER-2/neu, Muc-1, Ep-CAM-1, and p53 were recognized by the CTL clones generated. Our findings underscore that breast cancer is an immunogenic tumor and that HLA-class I-matched allogeneic tumor cells can be used as stimulator cells to generate tumor-specific CTL from peripheral blood of a breast cancer patient with specificity for an antigenic determinant that is broadly expressed on tumor cells from various origins or with specificity limited to the breast cancer stimulator cell.
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PMID:Isolation of broadly reactive, tumor-specific, HLA Class-I restricted CTL from blood lymphocytes of a breast cancer patient. 1062 33

Development of acquired resistance against antiestrogen treatment is a serious problem in human breast cancer, and knowledge of alterations resulting in resistance is important for selection of further treatment. To mimic the clinical situation we have established a series of MCF-7 human breast cancer cell lines by long term treatment with the antiestrogens tamoxifen, ICI 164,384, and ICI 182,780. Common for these cell lines is a decreased expression of the estrogen receptor alpha (ER alpha). In human breast cancer, lack of response to endocrine therapy is often associated with decreased expression of the estrogen receptor and increased expression of epidermal growth factor receptor (EGFR) and/or HER-2/neu (ErbB-2). Our antiestrogen resistant cell lines did not express altered levels of EGFR, HER-2/neu, ErbB-3, or ErbB-4. Estrogen and antiestrogen regulation of HER-2/neu expression was essentially similar in parent and resistant MCF-7 cells. Treatment with antibodies to HER-2/neu (Herceptin) did not affect growth of MCF-7 cells or resistant cells, indicating that in this in vitro model system, acquired antiestrogen resistance does not emerge from activation of the HER-2/neu signaling pathway. In MCF-7 cells transfected with HER-2/neu and/or ErbB-3, overexpression alone did not result in resistance. However, addition of heregulinl-beta1 abolished the inhibitory activity of ICI 182,780 on both vector and HER-2/neu/ErbB-3 transfected MCF-7 cells, demonstrating that activation of the HER-2/neu receptor signaling pathway can override the growth inhibitory effect of ICI 182,780.
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PMID:Acquired antiestrogen resistance in MCF-7 human breast cancer sublines is not accomplished by altered expression of receptors in the ErbB-family. 1063 17

Nuclear steroid/thyroid/retinoid receptors and c-erbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple c-erbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via cross-connected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and c-erbB-2, and between ER and retinoic acid receptor(RAR)-alpha have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12-O-tetradecanoylphorbol-13-acetate, TPA), on growth and expression of c-erbB and RARs in MCF-7 breast cancer cells, which contain high levels of RAR-alpha and -gamma, and which express significant amounts of c-erbB-2 and -3. All trans-retinoic acid (tRA), the anti-estrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17beta-estradiol (E2) stimulated cell growth. Flow cytometry revealed that tRA and E2 reduced c-erbB-2 and -3, whereas tamoxifen, Forsk and TPA up-regulated c-erbB-2. c-erbB-3 was co-regulated with c-erbB-2. Northern analysis demonstrated that RAR-alpha was down-regulated by dexamethasone, ICI, and TPA, whereas vitamin D3 and E2 up-regulated RAR-alpha. RAR-gamma expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and c-erbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.
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PMID:Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c-erbB and retinoic acid receptor expression in MCF-7 breast cancer cells. 1067 83

HER-2/neu is overexpressed in 25-30% of human breast cancers. We prepared an anti-HER-2/neu hammerhead ribozyme expressed by a recombinant adenovirus (rAdHER-Rz). Human breast cancer cell lines were transduced with high efficiency, resulting in decreased HER-2/neu expression. In vivo injections of rAdHER-Rz into BT-474 tumors established in nude mice inhibited tumor growth to 20% of mock-treated controls. Similar in vivo effects were shown in MCF-7 cells, which do not overexpress HER-2/neu. The growth inhibitory effects of rAdHER-Rz were greater than those of an antisense-expressing vector. These results suggest the utility of anti-HER-2/neu ribozymes as a rational strategy for gene therapy of breast cancer. Gene Therapy (2000) 7, 241-248.
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PMID:Adenovirus-mediated ribozyme targeting of HER-2/neu inhibits in vivo growth of breast cancer cells. 1069 1

We have tested the sensitivity of human MCF-10A mammary epithelial cells and of their transformed derivatives overexpressing an activated c-Ha-ras gene (MCF-10A Ha-ras cells), the c-erbB-2 gene (MCF-10A c-erbB-2 cells) or both genes (MCF-10A HE cells) to different cytotoxic drugs. As compared with parental MCF-10A cells, the transformed cells exhibited an increased sensitivity to topoisomerase I- and topoisomerase II-inhibitors, and to platinum-derivatives with a 2- to 10-fold reduction in IC(50) values. A remarkable difference in sensitivity was observed following treatment with taxanes. While MCF-10A Ha-ras cells showed an increased sensitivity, MCF-10A c-erbB-2 and MCF-10A HE cells exhibited a relative resistance to taxol and taxotere, with an approximately 3.5- to 6.5-fold higher IC(50) as compared with MCF-10A cells suggesting that c-erbB-2 overexpression has a dominant effect compared with an activated c-Ha-ras gene. The type I cAMP-dependent protein kinase (PKAI) is overexpressed in cancer cells. Inhibition of PKAI by antisense oligonucleotides targeting its RIalpha regulatory subunit results in cancer cell growth inhibition. To evaluate the effect of blocking PKAI on MCF-10A cell sensitivity to taxanes, we treated these cells with taxol or taxotere in combination with a PKAI antisense oligonucleotide. Treatment with this agent, but not with a control scramble sequence, was able to overcome the effect of c-erbB-2 overexpression on MCF-10A cell sensitivity to taxol and taxotere, with a 20- to 40-fold shift in the IC(50) values for the 2 drugs.
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PMID:Resistance to taxanes is induced by c-erbB-2 overexpression in human MCF-10A mammary epithelial cells and is blocked by combined treatment with an antisense oligonucleotide targeting type I protein kinase A. 1069 53

Estrogen induced erbB-2 tyrosine kinase activity in human breast epithelial cells irrespective of estrogen receptor expression. MCF10A is an immortal normal human breast epithelial cell line which does not express estrogen receptor. After treatment of MCF10A cells with estradiol-17beta (E2), a phosphorylated 90 kDa protein which co-immunoprecipitates with p185erbB-2 is detected. The response is transient, detected after 1-5 min exposure to E2, and dose dependent, occurring at 10-10 M E2. A similar response was observed for MCF10A cells transfected with an estrogen receptor, estrogen receptor expressing MCF-7 cells, and estrogen receptor-negative MDA-MB-435 cells but at 10-11 M E2. Overexpression of c-erbB-2 in MCF10A cells prolonged the phosphorylated p90 response to E2.
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PMID:Tyrosine phosphorylation of an erbB-2 related p90 protein induced by estrogen in human breast epithelial cells. 1076 42

The ErbB receptor tyrosine kinase family consists of the epidermal growth factor (EGF) receptor (ErbB1) and three related receptors (ErbB2, ErbB3, ErbB4). Their intrinsic tyrosine kinases can be activated by receptor-dimerization induced by numerous ligands or overexpression. ErbB receptors are frequently overexpressed in breast cancer, and their overexpression is associated with protection from apoptosis. To directly assess their role in apoptosis sensitivity of breast cancer cells, we established MCF-7 breast carcinoma cell lines overexpressing each ErbB receptor alone or in all possible pairs. Overexpression of ErbB1, ErbB2 and ErbB4 receptors was enough to activate them as judged by their phosphorylation, whereas co-expression of other ErbB receptors was necessary for the phosphorylation of the ErbB3. Surprisingly, overexpression of the ErbB receptors even when combined with treatment with their ligands (EGF, transforming growth factor alpha, betacellulin, neuregulins) failed to protect the MCF-7 cells from cell death induced by either tumor necrosis factor (TNF) or serum starvation. During starvation TGF-alpha, however, increased the cell size of the ErbB1 overexpressing cell line, and neuregulin1-beta1 increased that of all cell lines. In conclusion, our data does not support the role of ErbB receptors in the regulation of cell death induced by TNF or serum starvation, and the observed association in breast cancer may be due to other concomitant changes.
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PMID:Cell death induced by TNF or serum starvation is independent of ErbB receptor signaling in MCF-7 breast carcinoma cells. 1079 81

The neu differentiation factors/heregulins (HRGs) comprise a family of polypeptide growth factors that activate p185(erbB-2) through direct binding to either erbB-3 or erbB-4 receptor tyrosine kinases. We have previously shown that HRG-beta is mitogenic for various human mammary epithelial cell lines that coexpress c-erbB-2 and c-erbB-3. Phosphatidylinositol 3-kinase (PI3K) is activated by p185(erbB-2) /erbB-3 heterodimers in cells stimulated by HRG, and PI3K is constitutively activated by p185(erbB-2) /erbB-3 in breast carcinoma cells that overexpress c-erbB-2. To better understand the relative abilities of HRGs, epidermal growth factor (EGF), or insulin to activate PI3K under normal physiological conditions, we compared the levels of recruitment of the 85-kDa regulatory subunit of PI3K when activated by the type I (erbB) or type II [insulin-like growth factor (IGF)] receptor tyrosine kinases in two different nontransformed human mammary epithelial cell lines. The nontransformed H16N-2 cells isolated from normal tissue express EGFR, p185(erbB-2), and erbB-3, and are highly responsive to the mitogenic effects of HRG-beta as well as to the combination of EGF and insulin in serum-free culture. We measured the stoichiometry of p85 recruited by tyrosine-phosphorylated proteins induced in H16N-2 cells by either the alpha or the beta isoform of HRG. HRG-beta was greater than 10-fold more potent in inducing p85 recruitment than was the less biologically active HRG-alpha isoform. HRG-beta was also a more potent inducer of p85 recruited by tyrosine-phosphorylated proteins than was either EGF, insulin, or EGF and insulin combined. Furthermore, erbB-3 principally mediated the direct recruitment of p85 in cells stimulated by HRG or EGF, indicating that, in addition to the high-level activation of PI3K by p185(erbB-2) / erbB-3, EGFR/erbB-3 heterodimer interaction is essential for the weak but significant level of PI3K activated by EGF in cells that express normal EGFR levels. Studies using the PI3K inhibitor wortmannin also indicated that PI3K activation was required for the proliferation of H16N-2 cells induced by either HRG-beta or EGF and insulin in serum-free culture. Finally, HRG-beta was also an especially potent inducer of PI3K in the nontransformed MCF-10A cells, which were derived spontaneously from normal reduction mammoplasty tissue. These data show, for the first time, a side-by-side quantitative comparison of the relative degree of PI3K activated by different growth factors in nontransformed growth factor-dependent cells under precisely defined conditions in culture.
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PMID:Heregulin-beta is especially potent in activating phosphatidylinositol 3-kinase in nontransformed human mammary epithelial cells. 1079 4


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