Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells.
16 Jan 2004-Biochemical and Biophysical Research Communications (Biochem Biophys Res Commun)-Vol. 313, Iss: 3, pp 709-715
TL;DR: Data provided are consistent with the view that the IGF-IR mediated attenuation of trastuzumab-induced growth inhibition is dependent on IGF-I-induced PI3K signaling rather than IGF-i-induced MAPK signaling.
About: This article is published in Biochemical and Biophysical Research Communications.The article was published on 2004-01-16. It has received 32 citations till now. The article focuses on the topics: MAPK/ERK pathway & Shc Signaling Adaptor Proteins.
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TL;DR: This review focuses on synergistic therapeutic systems combining gene regulation and photothermal ablation as well as logically designed nano-carriers aimed at enhancing the delivery efficiency of therapeutic genes using the photothermal effect.
206 citations
TL;DR: During skeletal muscle development, the expression level of ssc-miR-378 was low at 33 days post-coitus (dpc), increased at 65 and 90 dpc, peaked at postnatal day 0, and finally declined and maintained a comparatively stable level, which suggested that ssc -miR -378 was a new candidate miRNA for myogenesis and participated in skeletal Muscle development in pigs.
Abstract: MicroRNAs (miRNAs) are short, single-stranded non-coding RNAs that repress their target genes by binding their 3′ UTRs. These RNAs play critical roles in myogenesis. To gain knowledge about miRNAs involved in the regulation of myogenesis, porcine longissimus muscles were collected from 18 developmental stages (33-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, 100- and 105-day post-gestation fetuses, 0 and 10-day postnatal piglets and adult pigs) to identify miRNAs using Solexa sequencing technology. We detected 197 known miRNAs and 78 novel miRNAs according to comparison with known miRNAs in the miRBase (release 17.0) database. Moreover, variations in sequence length and single nucleotide polymorphisms were also observed in 110 known miRNAs. Expression analysis of the 11 most abundant miRNAs were conducted using quantitative PCR (qPCR) in eleven tissues (longissimus muscles, leg muscles, heart, liver, spleen, lung, kidney, stomach, small intestine and colon), and the results revealed that ssc-miR-378, ssc-miR-1 and ssc-miR-206 were abundantly expressed in skeletal muscles. During skeletal muscle development, the expression level of ssc-miR-378 was low at 33 days post-coitus (dpc), increased at 65 and 90 dpc, peaked at postnatal day 0, and finally declined and maintained a comparatively stable level. This expression profile suggested that ssc-miR-378 was a new candidate miRNA for myogenesis and participated in skeletal muscle development in pigs. Target prediction and KEGG pathway analysis suggested that bone morphogenetic protein 2 (BMP2) and mitogen-activated protein kinase 1 (MAPK1), both of which were relevant to proliferation and differentiation, might be the potential targets of miR-378. Luciferase activities of report vectors containing the 3′UTR of porcine BMP2 or MAPK1 were downregulated by miR-378, which suggested that miR-378 probably regulated myogenesis though the regulation of these two genes.
77 citations
Cites background from "Overexpression of ErbB2 receptor in..."
...Phosphorylated Shc, when combined with the GRB2-SOS complex, activates the Ras/Raf/ MAPK pathway, which leads to mitogenesis [15]....
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TL;DR: Comparison of FISH and qPCR together with immunohistochemistry shows thatqPCR is more sensitive to detect HER-2/neu gene amplification in tumors scored as 2+ with immun ohistochemistry, but the diagnostic cut-off ratio should be defined above 2.7 to avoid high number of false positive cases.
Abstract: The aim of our study was to evaluate the value of quantitative real-time-PCR (qPCR) in the determination of HER-2/neu amplification status of human breast carcinomas by comparing qPCR, FISH and immunohistochemistry results from the same samples. A total of 210 breast carcinomas were examined. Ready-to-use CB11 antibody was applied to detect HER-2/neu oncoprotein expression. In 76 out of 210 cases FISH was performed, and 162 cases were investigated with qPCR. Seventy-five tumors were 2+ or 3+ positive with immunohistochemistry, while 135 samples were either completely negative or 1+. In 45 cases results from all three methods were available. Out of these, in twenty negative and sixteen positive cases both FISH and qPCR led to similar results. The mean qPCR amplification ratio in the concordant positive cases was 5.424 while in the qPCR+/FISH-group the mean ratio was 2.765. Out of 121 samples with scores of 0 or 1+ immunohistochemical result, analyzed also with qPCR, 26 showed HER-2/neu gene amplification. In these cases the mean amplification ratio was 2.53. Comparison of FISH and qPCR together with immunohistochemistry shows that qPCR is more sensitive to detect HER-2/neu gene amplification in tumors scored as 2+ with immunohistochemistry, but the diagnostic cut-off ratio should be defined above 2.7 to avoid high number of false positive cases. Amongst the immunohistochemistry score 2+ cases, 10 of 18 showed gene amplification by qPCR while 10 of 26 by FISH. In conclusion, a well calibrated HER-2/neu qPCR assay may serve as useful alternative to FISH in breast cancer patients.
74 citations
TL;DR: Trastuzumab, an anti-HER2 monoclonal antibody, improves outcome in women with early and metastatic breast cancer and develops of modulators of immune checkpoints.
Abstract: Breast cancers over-express the human epidermal growth factor receptor 2 (HER2) in about 15% of patients. This transmembrane tyrosine kinase receptor activates downstream signaling pathways and leads to proliferation of cancer cells. Trastuzumab, an anti-HER2 monoclonal antibody, improves outcome in women with early and metastatic breast cancer. Resistance to trastuzumab involves the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, truncation of the Her2 receptor or lack of immune response. The last decade has seen major advances in strategies to overcome resistance to trastuzumab. This includes the development of antibody-drug conjugates, dual HER2 inhibition strategies, inhibition of PI3K/mTOR pathway and development of modulators of immune checkpoints.
68 citations
Cites background from "Overexpression of ErbB2 receptor in..."
...Its antitumor activity is hypothesized to be related to two different mechanisms of action: downregulation of the intracellular signaling pathway via the PI3K and MAPK pathways, and activation of the immune response via antibody dependent cell-mediated cytotoxicity (ADCC) and eventually adaptive immune response [19-22]....
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TL;DR: A simple model based on the Boolean network model combined with stochastic propagation of the signal provides a valuable first step in modeling signaling networks, but to obtain a fully predictive model, more detailed knowledge regarding parameters of individual interactions might be necessary.
Abstract: Background
Cellular response to external stimuli requires propagation of corresponding signals through molecular signaling pathways. However, signaling pathways are not isolated information highways, but rather interact in a number of ways forming sophisticated signaling networks. Since defects in signaling pathways are associated with many serious diseases, understanding of the crosstalk between them is fundamental for designing molecularly targeted therapy. Unfortunately, we still lack technology that would allow high throughput detailed measurement of activity of individual signaling molecules and their interactions. This necessitates developing methods to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Furthermore, absence of the reaction coefficients necessary for detailed modeling of signal propagation raises the question whether simple parameter-free models could provide useful information about such pathways.
62 citations
Cites background from "Overexpression of ErbB2 receptor in..."
...2003 [28] The authors showed that in breast cancer cells with high levels of HER2 expression, signaling from IGF to Erk1/2 was attenuated, and this inhibition was reversed after the number of HER2 had been lowered by treatment with shRNA....
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References
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TL;DR: Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer, and had greater prognostic value than most currently used prognostic factors in lymph node-positive disease.
Abstract: The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.
11,597 citations
"Overexpression of ErbB2 receptor in..." refers background in this paper
...Overexpression of ErbB2 has been found in one-third of breast cancer patients and correlates with a higher relapse rate and poor clinical prognosis [2,25,26]....
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TL;DR: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion.
Abstract: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion. The network is often dysregulated in cancer and lends credence to the mantra that molecular understanding yields clinical benefit: over 25,000 women with breast cancer have now been treated with trastuzumab (Herceptin), a recombinant antibody designed to block the receptor ErbB2. Likewise, small-molecule enzyme inhibitors and monoclonal antibodies to ErbB1 are in advanced phases of clinical testing. What can this pathway teach us about translating basic science into clinical use?
6,462 citations
"Overexpression of ErbB2 receptor in..." refers background in this paper
...The activation of ErbB2 by the formation of heterodimers with other ErbB receptors is well described [3–5] and involves prolongation of the signaling by ErbB2-containing heterodimers [6–9]....
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...Although no direct ligand has been found for ErbB2, it can be activated by its overexpression or transactivated by various ligands of EGF family [3]....
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...007 PI3K/Akt are two downstream pathways of ErbB2, which link ErbB2 to its biological functions [3]....
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TL;DR: How oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity is emphasized and an update is provided on the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies.
Abstract: Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans Their activity is normally tightly controlled and regulated Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in oncogenic PTK signalling This review emphasizes how oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies
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TL;DR: Deregulated cell proliferation provides a minimal 'platform' necessary to support further neoplastic progression and should be targeted withroit targeting to have potent and specific therapeutic consequences.
Abstract: Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences
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TL;DR: Analysis of the multiple processes that modulate EGFR signal transduction has revealed new therapeutic opportunities and elucidated mechanisms contributing to the efficacy of existing anticancer treatments.
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