ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti‐cancer therapy

Clinical and experimental data suggest that ErbB‐4, a member of the epidermal growth factor receptor family, may have a role in cancer progression and response to treatment. We found recently, using a retrospective clinical analysis, that expression of ErbB‐4 receptor is correlated with metastatic potential and patient survival in non‐small‐cell lung cancer (NSCLC). The purpose of this work was to correlate the expression of the ErbB‐4 and lung cancer cells growth in vitro and in vivo and to determine the therapeutic potential of a monoclonal antibody to ErbB‐4 against lung cancer. For this aim, we ectopically expressed ErbB‐4 in a human NSCLC cell line that did not express the ErbB‐4 protein. Overexpression of ErbB‐4 produced a constitutively activated ErbB‐4 receptor. The transfected ErbB‐4 positive clones showed an increased cell proliferation in vitro and in vivo in comparison with parental ErbB‐4 negative cells and with the cells transfected by neomycin‐resistant gene. A monoclonal antibody to ErbB‐4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB‐4. The results of the current study provide evidence that ErbB‐4 plays a significant role in human lung cancer and may serve as a molecular target for anticancer therapy. © 2006 Wiley‐Liss, Inc.

[1]  Y. Yarden,et al.  Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Ardizzoni,et al.  Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. , 2004, Current medicinal chemistry. Anti-cancer agents.

[3]  J. R. Reeves,et al.  Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer , 2003, The Journal of pathology.

[4]  B. Angus,et al.  Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-erbB-4 , 2003, Journal of clinical pathology.

[5]  D. Riese,et al.  A constitutively active ErbB4 mutant inhibits drug-resistant colony formation by the DU-145 and PC-3 human prostate tumor cell lines. , 2003, Cancer letters.

[6]  G. Carpenter,et al.  ErbB-4: mechanism of action and biology. , 2003, Experimental cell research.

[7]  T. Curran,et al.  ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[8]  M. Inbar,et al.  ErbB-4 expression in limb soft-tissue sarcoma: correlation with the results of neoadjuvant chemotherapy. , 2002, European journal of cancer.

[9]  J. Nesland,et al.  EGFR family expression in breast carcinomas. c‐erbB‐2 and c‐erbB‐4 receptors have different effects on survival , 2002, The Journal of pathology.

[10]  R. Allibone,et al.  Novel ERBB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma , 2001, Genes, chromosomes & cancer.

[11]  J. Greif,et al.  Correlation between c-erbB-4 receptor expression and response to gemcitabine-cisplatin chemotherapy in non-small-cell lung cancer. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  J. Smyth,et al.  Expression of erbB-4/HER-4 growth factor receptor isoforms in ovarian cancer. , 2001, Cancer research.

[13]  O. Stoeltzing,et al.  Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer , 2000, British Journal of Cancer.

[14]  R. Narayanan,et al.  HER-2/neu expression in archival non-small cell lung carcinomas using FDA-approved Hercep test. , 2000, Anticancer research.

[15]  M. Klagsbrun,et al.  A Natural ErbB4 Isoform That Does Not Activate Phosphoinositide 3-Kinase Mediates Proliferation but Not Survival or Chemotaxis* , 2000, The Journal of Biological Chemistry.

[16]  D. Barnes,et al.  Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. , 2000, Cancer research.

[17]  D. Stern,et al.  Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. , 1999, American journal of physiology. Heart and circulatory physiology.

[18]  M. Sliwkowski,et al.  Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells , 1999, Oncogene.

[19]  W. Gullick,et al.  Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 Growth Factor Receptors and Their Ligands, Neuregulin-1 α, Neuregulin-1 β, and Betacellulin, in Normal Endometrium and Endometrial Cancer , 1999 .

[20]  H. Friess,et al.  ErbB‐4 mRNA expression is decreased in non‐metastatic pancreatic cancer , 1999, International journal of cancer.

[21]  M. Kraus,et al.  Immune responses to all ErbB family receptors detectable in serum of cancer patients , 1999, Oncogene.

[22]  I. Ellis,et al.  c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer , 1998, Oncogene.

[23]  J. Lunec,et al.  Expression of the ErbB-neuregulin signaling network during human cerebellar development: implications for the biology of medulloblastoma. , 1998, Cancer research.

[24]  R. Poulsom,et al.  Expression of the c‐erbB‐4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types , 1998, The Journal of pathology.

[25]  L. Norton,et al.  Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. , 1998, Cancer research.

[26]  R. Sutherland,et al.  Granulosa cell tumors express erbB4 and are sensitive to the cytotoxic action of heregulin-beta2/PE40. , 1998, Cancer research.

[27]  D. Stern,et al.  Activation of ErbB4 by the Bifunctional Epidermal Growth Factor Family Hormone Epiregulin Is Regulated by ErbB2* , 1998, The Journal of Biological Chemistry.

[28]  K. Kelly,et al.  New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

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

[30]  M. Klagsbrun,et al.  Activation of HER4 by heparin‐binding EGF‐like growth factor stimulates chemotaxis but not proliferation , 1997, The EMBO journal.

[31]  O. Bogler,et al.  A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. , 1996, Cancer research.

[32]  Y. Yarden,et al.  Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. , 1996, Oncogene.

[33]  Y. Yarden,et al.  An Immunological Approach Reveals Biological Differences between the Two NDF/Heregulin Receptors, ErbB-3 and ErbB-4 (*) , 1996, The Journal of Biological Chemistry.

[34]  L. Akslen,et al.  Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas. , 1996, Cancer research.

[35]  Y. Yarden,et al.  Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. , 1996, The American journal of pathology.

[36]  T. van Raaij,et al.  Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta. , 1996, Oncogene.

[37]  W. Richards,et al.  Localized adenocarcinoma of the lung: oncogene expression of erbB-2 and p53 in 150 patients. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  Y. Yarden,et al.  Medullary carcinoma is associated with expression of intercellular adhesion molecule-1. Implication to its morphology and its clinical behavior. , 1994, The American journal of pathology.

[39]  E. Peles,et al.  ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. , 1994, The Journal of biological chemistry.

[40]  W. Cavenee,et al.  A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[41]  G. Plowman,et al.  Heregulin induces tyrosine phosphorylation of HER4/p180erbB4 , 1993, Nature.

[42]  G. Plowman,et al.  Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  D. Weiner,et al.  p185neu expression in human lung adenocarcinomas predicts shortened survival. , 1990, Cancer research.

[44]  F. Hamdy,et al.  THE NEW ENGLAND JOURNAL OF MEDICINE , 1977, The Lancet.

[45]  Taylor Murray,et al.  Cancer Statistics, 2001 , 2001, CA: a cancer journal for clinicians.

[46]  H. Juhl,et al.  Comparative analysis of the EGF-receptor family in pancreatic cancer: expression of HER-4 correlates with a favourable tumor stage. , 2001, International journal of surgical investigation.

[47]  Y. Yarden,et al.  Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. , 2000, Advances in cancer research.

[48]  M. O’Connor-McCourt,et al.  Expression of P185erbB-2, P160erbB-3, P180erbB-4, and heregulin alpha in human normal bronchial epithelial and lung cancer cell lines. , 1999, Anticancer research.

[49]  M. Melhem,et al.  Tissue expression of neu differentiation factor/heregulin and its receptor complex in prostate cancer and its biologic effects on prostate cancer cells in vitro. , 1997, The cancer journal from Scientific American.

[50]  M. Kelley,et al.  Genetic mechanisms of solid tumor oncogenesis. , 1994, Advances in internal medicine.

[51]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.