Mechanisms for oncogenic activation of the epidermal growth factor receptor.

The Epidermal growth factor receptor (EGFR) is a membrane spanning glycoprotein, which frequently has been implicated in various cancer types. The mechanisms by which EGFR becomes oncogenic are numerous and are often specific for each cancer type. In some tumors, EGFR is activated by autocrine/paracrine growth factor loops, whereas in others activating mutations promote EGFR signaling. Overexpression and/or amplification of the EGFR gene are prevalent in many cancer types leading to aberrant EGFR signaling. In addition, failure to attenuate receptor signaling by receptor downregulation can also lead to cellular transformation. Heterodimerization of EGFR with ErbB2 inhibits downregulation of EGFR and thereby prolongs growth factor signaling. This also indicates that cross-talk between EGFR and heterologous receptor systems serves as another mechanism for oncogenic activation of EGFR. Because of its role in tumor promotion, the EGFR has been intensely studied as a therapeutic target. There are currently two major mechanisms by which the EGFR is targeted: antibodies binding to the extracellular domain of EGFR and small-molecule tyrosine-kinase inhibitors. However, tumorigenesis is a multi-step process involving several mutations, which might explain why EGFR therapeutics has only been partially successful. This highlights the importance of pinpointing the mechanisms by which EGFR becomes oncogenic in a particular cancer. In this review, each of the above mentioned mechanisms will be discussed, as a detailed molecular and genetic understanding of how EGFR contributes to the malignant phenotype might offer new promise for the design, development and clinical evaluation of future tumor-specific anticancer approaches.

[1]  Wenjun Guo,et al.  Integrin signalling during tumour progression , 2004, Nature Reviews Molecular Cell Biology.

[2]  L. E. Johannessen,et al.  The inhibitory effect of ErbB2 on epidermal growth factor-induced formation of clathrin-coated pits correlates with retention of epidermal growth factor receptor-ErbB2 oligomeric complexes at the plasma membrane. , 2005, Molecular biology of the cell.

[3]  C. Futter,et al.  Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes , 1996, The Journal of cell biology.

[4]  E. Olapade-Olaopa,et al.  Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer , 1999, British Journal of Cancer.

[5]  B. van Deurs,et al.  EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes. , 2007, Carcinogenesis.

[6]  R. Epstein,et al.  Overexpression of ErbB2 impairs ligand‐dependent downregulation of epidermal growth factor receptors via a post‐transcriptional mechanism , 1999, Journal of cellular biochemistry.

[7]  T. Seidal,et al.  The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian carcinoma , 2000, International Journal of Gynecologic Cancer.

[8]  J. Biegel,et al.  Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. , 1995, Cancer research.

[9]  D. Bigner,et al.  EGF mutant receptor vIII as a molecular target in cancer therapy. , 2001, Endocrine-related cancer.

[10]  P. Leedman,et al.  The Evolution of Complexity , 1995 .

[11]  F. Hirsch,et al.  Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  A. Ullrich,et al.  The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. , 2001, Endocrine-related cancer.

[13]  D. Goeddel,et al.  Expression in rat fibroblasts of a human transforming growth factor-α cDNA results in transformation , 1986, Cell.

[14]  M. Sliwkowski,et al.  Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). , 1999, Seminars in oncology.

[15]  R. Palmiter,et al.  Overexpression of TGFα in transgenic mice: Induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast , 1990, Cell.

[16]  L. Silengo,et al.  Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion‐dependent cell survival , 1998, The EMBO journal.

[17]  Daniel A. Haber,et al.  Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways , 2004, Science.

[18]  C. Tacchetti,et al.  Integrin-induced Epidermal Growth Factor (EGF) Receptor Activation Requires c-Src and p130Cas and Leads to Phosphorylation of Specific EGF Receptor Tyrosines* , 2002, The Journal of Biological Chemistry.

[19]  N. Hynes,et al.  The ErbB receptors and their role in cancer progression. , 2003, Experimental cell research.

[20]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[21]  A. Ullrich,et al.  Ligand activation of overexpressed epidermal growth factor receptors transforms NIH 3T3 mouse fibroblasts. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Ullrich,et al.  Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors , 1996, Nature.

[23]  Michael Kofler,et al.  The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. , 2003, Molecular cell.

[24]  P. Humphrey,et al.  Structural alterations of the epidermal growth factor receptor gene in human gliomas. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[25]  K. Kinzler,et al.  Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Analysis of genomic rearrangements associated with EGRFvIII expression suggests involvement of Alu repeat elements. , 2000, Neuro-oncology.

[27]  J. Isola,et al.  Allelic length of a CA dinucleotide repeat in the egfr gene correlates with the frequency of amplifications of this sequence—first results of an inter‐ethnic breast cancer study , 2004, The Journal of pathology.

[28]  C. Cordon-Cardo,et al.  Expression of transforming growth factor-alpha and the epidermal growth factor receptor in human prostate tissues. , 1994, The Journal of urology.

[29]  Ruo-Pan Huang,et al.  Hydrogen peroxide promotes transformation of rat liver non‐neoplastic epithelial cells through activation of epidermal growth factor receptor , 2001, Molecular carcinogenesis.

[30]  B. Steinberg,et al.  Elevation of the epidermal growth factor receptor and dependent signaling in human papillomavirus-infected laryngeal papillomas. , 1999, Cancer research.

[31]  H. P. Fell,et al.  Betacellulin-Pseudomonas toxin fusion proteins bind but are not cytotoxic to cells expressing HER4; correlation of EGFR for cytotoxic activity , 1998, Oncogene.

[32]  M. Berger,et al.  Progress Report of a Phase I Study of the Intracerebral Microinfusion of a Recombinant Chimeric Protein Composed of Transforming Growth Factor (TGF)-α and a Mutated form of the Pseudomonas Exotoxin Termed PE-38 (TP-38) for the Treatment of Malignant Brain Tumors , 2003, Journal of Neuro-Oncology.

[33]  M. Ciesielski,et al.  Deletion and tandem duplication of exons 2–7 in the epidermal growth factor receptor gene of a human malignant glioma , 2000, Oncogene.

[34]  A. Ullrich,et al.  Lysophosphatidic acid-induced squamous cell carcinoma cell proliferation and motility involves epidermal growth factor receptor signal transactivation. , 2002, Cancer research.

[35]  Jennifer L Hunt,et al.  Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting , 2006, Clinical Cancer Research.

[36]  A. Friedman,et al.  Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  P. Jeffrey,et al.  Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. , 2005, Cancer cell.

[38]  T. Joh,et al.  IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells. , 2005, Cytokine.

[39]  T. Hunter,et al.  The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. , 1999, Science.

[40]  T. K. Yeung,et al.  Endocytosis deficiency of epidermal growth factor (EGF) receptor-ErbB2 heterodimers in response to EGF stimulation. , 1999, Molecular biology of the cell.

[41]  K. Wiman,et al.  Small molecules that reactivate mutant p53. , 2003, European journal of cancer.

[42]  Manuel Hidalgo,et al.  An Epidermal Growth Factor Receptor Intron 1 Polymorphism Mediates Response to Epidermal Growth Factor Receptor Inhibitors , 2004, Cancer Research.

[43]  V. Rao,et al.  Epidermal Growth Factor Receptor-Dependent Regulation of Integrin-Mediated Signaling and Cell Cycle Entry in Epithelial Cells , 2004, Molecular and Cellular Biology.

[44]  Chan Zeng,et al.  Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  N. Pedersen,et al.  AND MUTANT , 2005 .

[46]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[47]  C. James,et al.  Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. , 2000, Cancer research.

[48]  Douglas R Lowy,et al.  E‐cadherin‐mediated adhesion inhibits ligand‐dependent activation of diverse receptor tyrosine kinases , 2004, The EMBO journal.

[49]  Takayuki Kosaka,et al.  Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  J. Pouysségur,et al.  Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Z. Kam,et al.  c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. , 1998, Genes & development.

[52]  W. Langdon,et al.  EGF receptor binding and transformation by v-cbl is ablated by the introduction of a loss-of-function mutation from the Caenorhabditis elegans sli-1 gene , 1997, Oncogene.

[53]  N. Goldstein,et al.  Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[54]  R. Kramer,et al.  Adhesion-mediated squamous cell carcinoma survival through ligand-independent activation of epidermal growth factor receptor. , 2004, The American journal of pathology.

[55]  V. Tkach,et al.  Expression of a naturally occurring constitutively active variant of the epidermal growth factor receptor in mouse fibroblasts increases motility , 2004, International journal of cancer.

[56]  S. Lipkowitz The role of the ubiquitination–proteasome pathway in breast cancer: Ubiquitin mediated degradation of growth factor receptors in the pathogenesis and treatment of cancer , 2002, Breast Cancer Research.

[57]  A. Wells,et al.  Epidermal growth factor receptor-mediated cell motility: phospholipase C activity is required, but mitogen-activated protein kinase activity is not sufficient for induced cell movement , 1994, The Journal of cell biology.

[58]  Y. Yarden,et al.  The role of ubiquitylation in signaling by growth factors: implications to cancer. , 2003, Seminars in cancer biology.

[59]  M. Maa,et al.  c-Src-mediated Phosphorylation of the Epidermal Growth Factor Receptor on Tyr845 and Tyr1101 Is Associated with Modulation of Receptor Function* , 1999, The Journal of Biological Chemistry.

[60]  C. Mamot,et al.  Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo. , 2005, Cancer research.

[61]  J. Boonstra,et al.  Hydrogen peroxide reversibly inhibits epidermal growth factor (EGF) receptor internalization and coincident ubiquitination of the EGF receptor and Eps15 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[62]  Yosef Yarden,et al.  Endocytosis of Receptor Tyrosine Kinases Is Driven by Monoubiquitylation, Not Polyubiquitylation* , 2003, Journal of Biological Chemistry.

[63]  K. Barrett,et al.  Carbachol-stimulated Transactivation of Epidermal Growth Factor Receptor and Mitogen-activated Protein Kinase in T84 Cells Is Mediated by Intracellular Ca2+, PYK-2, and p60 src * , 2000, The Journal of Biological Chemistry.

[64]  A. Fornace,et al.  Identification of an additional p53-responsive site in the human epidermal growth factor receptor gene promotor , 1997, Oncogene.

[65]  Silvia Benvenuti,et al.  Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. , 2005, The Lancet. Oncology.

[66]  Brian Higgins,et al.  Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. , 2002, Cancer cell.

[67]  J. Welsh,et al.  Ligand-induced transformation by a noninternalizing epidermal growth factor receptor. , 1990, Science.

[68]  D. Johnston,et al.  Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[69]  H. Friess,et al.  Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. , 1993, Anticancer research.

[70]  C. Macleod,et al.  Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[71]  A. Ullrich,et al.  Oxidative and Osmotic Stress Signaling in Tumor Cells Is Mediated by ADAM Proteases and Heparin-Binding Epidermal Growth Factor , 2004, Molecular and Cellular Biology.

[72]  R. Epstein,et al.  Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2 , 1997, Oncogene.

[73]  A. Ullrich,et al.  Signal characteristics of G protein‐transactivated EGF receptor , 1997, The EMBO journal.

[74]  S. Bishayee Role of conformational alteration in the epidermal growth factor receptor (EGFR) function. , 2000, Biochemical pharmacology.

[75]  M. Laburthe,et al.  Activation of proteinase-activated receptor 1 promotes human colon cancer cell proliferation through epidermal growth factor receptor transactivation. , 2004, Molecular cancer research : MCR.

[76]  Pier Paolo Di Fiore,et al.  Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation , 2003, Nature Cell Biology.

[77]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[78]  F. Cappuzzo,et al.  Epidermal Growth Factor Receptor Messenger RNA Expression, Gene Dosage, and Gefitinib Sensitivity in Non–Small Cell Lung Cancer , 2006, Clinical Cancer Research.

[79]  D. Bigner,et al.  Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). , 1997, The Biochemical journal.

[80]  E. Scholar,et al.  Role of Tyrosine Kinase Inhibitors in Cancer Therapy , 2005, Journal of Pharmacology and Experimental Therapeutics.

[81]  A. Lenferink,et al.  Differential endocytic routing of homo‐ and hetero‐dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers , 1998, The EMBO journal.

[82]  C. Arteaga Epidermal growth factor receptor dependence in human tumors: more than just expression? , 2002, The oncologist.

[83]  J. Minna,et al.  Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. , 2006, Cancer cell.

[84]  K. Kuroi,et al.  Prognostic significance of co-expression of c-erbB-2 oncoprotein and epidermal growth factor receptor in breast cancer patients. , 1992, American journal of surgery.

[85]  Hiroyuki Sakurai,et al.  Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas , 2005, Cancer.

[86]  M. Hidalgo,et al.  A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors , 2006, Clinical Cancer Research.

[87]  Zhong Jiang,et al.  Expression of transforming growth factor-α and epidermal growth factor receptor in gastrointestinal stromal tumours , 1999, Virchows Archiv.

[88]  R. Epstein,et al.  Transforming growth factor‐alpha short‐circuits downregulation of the epidermal growth factor receptor , 1999, Journal of cellular physiology.

[89]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[90]  H. Wiley,et al.  ErbB-2 Amplification Inhibits Down-regulation and Induces Constitutive Activation of Both ErbB-2 and Epidermal Growth Factor Receptors* , 1999, The Journal of Biological Chemistry.

[91]  A. Ullrich,et al.  GPCR-induced migration of breast carcinoma cells depends on both EGFR signal transactivation and EGFR-independent pathways , 2005, Biological chemistry.

[92]  Joseph Schlessinger,et al.  Ligand-Induced, Receptor-Mediated Dimerization and Activation of EGF Receptor , 2002, Cell.

[93]  M. Antonyak,et al.  Constitutive Activation of c-Jun N-terminal Kinase by a Mutant Epidermal Growth Factor Receptor* , 1998, The Journal of Biological Chemistry.

[94]  Melissa A. Wilson,et al.  A strong intronic enhancer element of the EGFR gene is preferentially active in high EGFR expressing breast cancer cells , 2001, Journal of cellular biochemistry.

[95]  W. Gerald,et al.  EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations , 2005, Modern Pathology.

[96]  D A Lauffenburger,et al.  Intracellular Trafficking of Epidermal Growth Factor Family Ligands Is Directly Influenced by the pH Sensitivity of the Receptor/Ligand Interaction (*) , 1995, The Journal of Biological Chemistry.

[97]  Morag Park,et al.  Escape from Cbl-mediated downregulation: a recurrent theme for oncogenic deregulation of receptor tyrosine kinases. , 2003, Cancer cell.

[98]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[99]  Y. Yarden,et al.  A mutant EGF‐receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling , 2002, The EMBO journal.

[100]  J. Baselga The EGFR as a target for anticancer therapy--focus on cetuximab. , 2001, European journal of cancer.

[101]  R. Nicholson,et al.  EGFR and cancer prognosis. , 2001, European journal of cancer.

[102]  S. Nakazawa,et al.  The Autocrine Loop of Epidermal Growth Factor Receptor‐Epidermal Growth Factor/Transforming Growth Factor‐α in Malignant Rhabdoid Tumor Cell Lines: Heterogeneity of Autocrine Mechanism in TTC549 , 2001, Japanese journal of cancer research : Gann.

[103]  S. Kuwada,et al.  Integrin α5/β1 Mediates Fibronectin-dependent Epithelial Cell Proliferation through Epidermal Growth Factor Receptor Activation , 2000 .

[104]  Hiroshi Asanuma,et al.  Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: Metalloproteinase inhibitors as a new therapy , 2002, Nature Medicine.

[105]  J. Boonstra,et al.  Hydrogen peroxide inhibits epidermal growth factor receptor internalization in human fibroblasts. , 2000, Free radical biology & medicine.

[106]  R H Perry,et al.  Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. , 1997, Cancer research.

[107]  S. Chrysogelos Chromatin structure of the EGFR gene suggests a role for intron 1 sequences in its regulation in breast cancer cells. , 1993, Nucleic acids research.

[108]  A Ciechanover,et al.  Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. , 1999, Molecular cell.

[109]  S. Deb,et al.  Transcriptional activation of the human epidermal growth factor receptor promoter by human p53 , 1996, Molecular and cellular biology.

[110]  Jae-Hoon Kim,et al.  Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains , 2002, Cell.

[111]  A. Friedman,et al.  Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor Receptor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme , 2004, Clinical Cancer Research.

[112]  K Dane Wittrup,et al.  Identification of the Epitope for the Epidermal Growth Factor Receptor-specific Monoclonal Antibody 806 Reveals That It Preferentially Recognizes an Untethered Form of the Receptor* , 2004, Journal of Biological Chemistry.

[113]  Jay H Lubin,et al.  Cooking oil fumes and risk of lung cancer in women in rural Gansu, China. , 2002, Lung cancer.

[114]  Monilola A. Olayioye,et al.  The ErbB receptor tyrosine family as signal integrators. , 2001, Endocrine-related cancer.

[115]  Monilola A. Olayioye,et al.  ErbB-1 and ErbB-2 Acquire Distinct Signaling Properties Dependent upon Their Dimerization Partner , 1998, Molecular and Cellular Biology.

[116]  Christian Klämbt,et al.  Epidermal growth factor receptor signaling , 2001, Current Biology.

[117]  Edouard C. Nice,et al.  Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor α , 2002, Cell.

[118]  Stefan Hart,et al.  TACE cleavage of proamphiregulin regulates GPCR‐induced proliferation and motility of cancer cells , 2003, The EMBO journal.

[119]  T. Ravid,et al.  Life and death decisions: ceramide generation and EGF receptor trafficking are modulated by oxidative stress. , 2005, Antioxidants & redox signaling.

[120]  H. Takamura,et al.  Interrelationship between transforming growth factor-alpha and epidermal growth factor receptor in advanced gastric cancer. , 1992, Oncology.

[121]  H. Poulsen,et al.  The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[122]  J. Siegfried,et al.  Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells. , 2005, Neoplasia.

[123]  Udo Greiser,et al.  Epidermal growth factor receptor (EGFR)-targeted immunoliposomes mediate specific and efficient drug delivery to EGFR- and EGFRvIII-overexpressing tumor cells. , 2003, Cancer research.

[124]  Y. Sagara,et al.  Co‐expression of epidermal growth factor receptor and transforming growth factor‐α predicts worse prognosis in breast‐cancer patients , 2000, International journal of cancer.

[125]  K. Zänker,et al.  Modulation of Epidermal Growth Factor Receptor Gene Transcription by a Polymorphic Dinucleotide Repeat in Intron 1* , 1999, The Journal of Biological Chemistry.

[126]  P. Humphrey,et al.  Deletion-mutant epidermal growth factor receptor in human gliomas: effects of type II mutation on receptor function. , 1991, Biochemical and biophysical research communications.

[127]  K. Carraway,et al.  Epidermal Growth Factor Receptor Activation under Oxidative Stress Fails to Promote c-Cbl Mediated Down-regulation* , 2002, The Journal of Biological Chemistry.

[128]  N. Pedersen,et al.  Analysis of the epidermal growth factor receptor specific transcriptome: Effect of receptor expression level and an activating mutation , 2005, Journal of cellular biochemistry.

[129]  E. Mittendorf,et al.  Investigating the Combination of Trastuzumab and HER2/neu Peptide Vaccines for the Treatment of Breast Cancer , 2006, Annals of Surgical Oncology.

[130]  Shih-Feng Tsai,et al.  High Frequency of Epidermal Growth Factor Receptor Mutations with Complex Patterns in Non–Small Cell Lung Cancers Related to Gefitinib Responsiveness in Taiwan , 2004, Clinical Cancer Research.

[131]  J. Last,et al.  EGF-Receptor phosphorylation and signaling are targeted by H2O2 redox stress. , 1998, American journal of respiratory cell and molecular biology.

[132]  A. Godwin,et al.  Expression of constitutively activated EGFRvlll in non‐small cell lung cancer , 2003, Cancer science.

[133]  A. Citri,et al.  Drug‐induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy , 2002, The EMBO journal.

[134]  T. Hunter Growth factors: The epidermal growth factor receptor gene and its product , 1984, Nature.

[135]  B. Karlan,et al.  Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[136]  Lee M Ellis,et al.  Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[137]  J. Siegfried,et al.  Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor , 2003, Oncogene.

[138]  Robert J. Lefkowitz,et al.  Role of c-Src Tyrosine Kinase in G Protein-coupled Receptorand Gβγ Subunit-mediated Activation of Mitogen-activated Protein Kinases* , 1996, The Journal of Biological Chemistry.