Phosphorylation of tyrosine 1248-ERBB2 measured by chemiluminescence-linked immunoassay is an independent predictor of poor prognosis in primary breast cancer patients

Cicenas, Jonas; Urban, Patrick; Küng, Willy; Vuaroqueaux, Vincent; Labuhn, Martin; Wight, Edward; Eppenberger, Urs; Eppenberger‐Castori, Serenella

doi:10.1016/j.ejca.2005.11.012

Cited by 57 publications

(46 citation statements)

References 22 publications

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“…However, the phosphorylated tyrosine 1248 of Her-2 was associated with BCR, suggesting that IHC evaluation of the phosphorylated form is better than the standard Her-2 test, which is not clinically used for prostate cancer patients because of a lack of reliability and association with outcome. Interestingly, similar results have been found in breast cancer tissue (Thor et al, 2000;Cicenas et al, 2006;Frogne et al, 2009) when staining of tyrosine 1221/1222 was compared with that of total Her-2. Further studies in larger cohorts would be necessary to validate this initial observation and determine the validity of phospho-Her-2 staining for clinical use in prostate cancer.…”

Section: Discussionsupporting

confidence: 69%

Hierarchical clustering of immunohistochemical analysis of the activated ErbB/PI3K/Akt/NF-κB signalling pathway and prognostic significance in prostate cancer

et al. 2010

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BACKGROUND: The PI3K/Akt signalling pathway, induced by epidermal growth factor receptor (EGFR) and Her-2, is involved in the constitutive activation of NF-kB in prostate cancer cell lines. In this study, we extended the in vitro observation using an ex vivo model of prostate cancer tissues and assessed the prognostic significance of the PI3K/Ak/NF-kB signalling determinants. METHODS: We analysed a prostate cancer tissue microarray of 63 patients for the expression of total and activated EGFR, Her-2 receptors and the signalling molecules PTEN, phospho-PTEN, Akt, phospho-Akt and the NF-kB subunit p65. Data were analysed using Spearman's rho test, Kaplan -Meier curves and multivariate Cox regression analysis. In addition, a non-supervised hierarchical clustering analysis was applied to stratify patients according to prognostic groups in terms of risk of recurrence. RESULTS: The concomitant overexpression of activated EGFR and Her-2 was correlated with the nuclear expression of NF-kB. EGFR, phospho-EGFR, phospho-Her-2, ErbB3 and nuclear NF-kB were associated with the overall biochemical recurrence (BCR) of patients. The non-supervised hierarchical clustering analysis resulted in the separation of patients into five groups according to BCR. CONCLUSIONS: These results validate the previous in vitro data on ErbB involvement in NF-kB activation and shows evidence for a significant role of ErbB/PI3K/Akt/NF-kB signalling in the progression of prostate cancer.

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Section: Discussionsupporting

confidence: 69%

Hierarchical clustering of immunohistochemical analysis of the activated ErbB/PI3K/Akt/NF-κB signalling pathway and prognostic significance in prostate cancer

et al. 2010

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“…Despite of early treatment with surgical and chemotherapy, women with disease having Her-2/neu amplification shows poor disease-free survival due to its aggressive form. [19][20][21][22] Many methods have been used to therapeutically target Her-2-overexpressing cancers, including the use of anti-Her-2/neu antibodies. [23][24][25][26] Trastuzumab also known as Herceptin for humanized form, was found to inhibit the proliferation of human cancer cells that overexpress Her-2/neu, both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model

et al. 2008

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The current gene transfer technology for single chain (scFv)-based chimeric immune receptor (CIR) has relied on retrovirus and lentivirus vectors which require a long time to obtain sufficient number of transduced cells and stably incorporate into genome. To ameliorate these limitations, we applied RNA electroporation to human peripheral blood lymphocytes (PBLs) activated with anti-CD3 antibody and interleukin-2 (IL-2) for 3 days and assessed that PBL transiently expressing anti-Her-2/neu CIR (CIR-PBL) containing signaling portion of CD28 and CD3z could elicit strong cytotoxicity in vitro and antitumor responses in vivo. The CIR-PBL expressed high level of CIR in CD4 þ , CD8 þ and CD56 þ cells. Her-2/neu-specific stimulation induced secretion of type-I cytokines including interferon-g (IFN-g), IL-8 and granulocyte-macrophage colony-stimulating factor, and IFN-g secretion was mainly mediated by CD8 þ T cells. CIR-PBL specifically killed SKOV3 cell line expressing Her-2/neu. Adoptive transfer of CIR-PBL in SKOV3 xenograft model led to significant inhibition of tumor growth compared with transfer of mock-transduced PBL and showed higher inhibition than those with Herceptin, humanized monoclonal antibody specific for Her-2/neu. These results provided evidence that electroporation of CIR RNA to human PBLs could be used for rapid generation and high number of therapeutic antigen-specific T cells for adoptive immunotherapy.

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“…Blotting with specific anti-phosphoErbB2 antibodies revealed that Muc4 expression induced the hyperphosphorylation of ErbB2 at Tyr-1248 and Tyr-877, sites that have been implicated in ErbB2 signaling (19,20). Importantly, tyrosine phosphorylation of ErbB2 at Tyr-1248 is an independent predictor of poor prognosis in human breast cancer (21).…”

Section: Muc4 Specifically Potentiates Nrg1␤-stimulated Erbb2mentioning

confidence: 99%

The Mucin Muc4 Potentiates Neuregulin Signaling by Increasing the Cell-surface Populations of ErbB2 and ErbB3

Funes

Miller

Lai

et al. 2006

Journal of Biological Chemistry

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Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1␤ (NRG1␤) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1␤ signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1␤ binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1␤ treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.The ErbB family of receptor tyrosine kinases includes ErbB1/ epidermal growth factor (EGF) 3 receptor, ErbB2/Her2/Neu, ErbB3, and ErbB4. The EGF-like growth factor family of ligands binds the extracellular domain of the ErbB receptors leading to the formation of both homo-and heterodimers. Receptor dimer formation is followed by autophosphorylation of receptor intracellular domains, recruitment of intracellular signaling proteins, and the initiation of a number of signaling cascades that regulate cellular growth, motility, and survival. ErbB receptors play critical roles both in development and tissue maintenance (1), and their overexpression and aberrant activation have been implicated in the genesis and progression of a variety of human tumors (2).While in general receptor heterodimerization is thought to diversify ErbB signaling (1), heterodimerization with ErbB2 is required for ErbB3 signaling in response to the neuregulin-1 (NRG1) growth factor. No soluble growth factor ligand has been identified that binds to ErbB2, but it is the preferred dimerization partner of the other ErbB family members. Thus, it is thought that its function is to heterodimerize with the other ErbB family members to enhance signaling. ErbB3 is a binding receptor for NRG1 but lacks intrinsic kinase activity (3) and is not capable of signaling on its own. The ErbB2-ErbB3 heterodimer efficiently activates the Ras/Erk pathway, and the C-terminal domain of ErbB3 contains six binding sites for the p85 subunit of PI3K that very efficiently couple the activated receptor ...

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Phosphorylation of tyrosine 1248-ERBB2 measured by chemiluminescence-linked immunoassay is an independent predictor of poor prognosis in primary breast cancer patients

Cited by 57 publications

References 22 publications

Hierarchical clustering of immunohistochemical analysis of the activated ErbB/PI3K/Akt/NF-κB signalling pathway and prognostic significance in prostate cancer

Hierarchical clustering of immunohistochemical analysis of the activated ErbB/PI3K/Akt/NF-κB signalling pathway and prognostic significance in prostate cancer

Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model

The Mucin Muc4 Potentiates Neuregulin Signaling by Increasing the Cell-surface Populations of ErbB2 and ErbB3

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