The ErbB2 Signaling Network as a Target for Breast Cancer Therapy

Overexpression of the ErbB2/Her2 receptor tyrosine kinase in breast cancers is associated with the most aggressive tumors. Experimental studies have revealed that ErbB2 shows many features of a therapeutic target: ErbB2 is able to confer many of the characteristics of a cancerous cell, including uncontrolled proliferation, resistance to apoptosis and increased motility; ErbB2 overexpression is specific to tumor cells; as a cell surface-associated protein, it is easily accessible to drugs and as a kinase it is amenable to targeted inhibition by small molecules. Recent clinical results demonstrate the efficacy of ErbB2-targeting therapy and promise an expanding use of ErbB2-targeting drugs for breast cancer treatment. However, as only a fraction of patients responds successfully to therapy and risks of recurrence are still high, further investigation is required for an improved understanding of the complex network of signaling pathways underlying ErbB2-driven cancer progression.

[1]  D B Evans,et al.  Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): increased invasiveness may contribute to poor prognosis. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  P. Pelicci,et al.  Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase. , 1995, Oncogene.

[4]  Dana M. Brantley-Sieders,et al.  Increased Malignancy of Neu-Induced Mammary Tumors Overexpressing Active Transforming Growth Factor β1 , 2003, Molecular and Cellular Biology.

[5]  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.

[6]  J. Feldner,et al.  Cancer cell motility--on the road from c-erbB-2 receptor steered signaling to actin reorganization. , 2002, Experimental cell research.

[7]  M. Sliwkowski,et al.  An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. , 2003, Molecular cell.

[8]  Greg Yothers,et al.  Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. , 2005, The New England journal of medicine.

[9]  C. A. Carraway,et al.  Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27kip, but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways , 2002, Oncogene.

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

[11]  J. Isola,et al.  Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. , 2005, Cancer research.

[12]  Andy J. Minn,et al.  Genes that mediate breast cancer metastasis to lung , 2005, Nature.

[13]  Frank E. Jones,et al.  The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone , 2004, The Journal of cell biology.

[14]  J. Mendelsohn,et al.  Heregulin Regulates Cytoskeletal Reorganization and Cell Migration through the p21-activated Kinase-1 via Phosphatidylinositol-3 Kinase* , 1998, The Journal of Biological Chemistry.

[15]  W. Gullick,et al.  Identification of c‐erbB‐3 binding sites for phosphatidylinositol 3′‐kinase and SHC using an EGF receptor/c‐erbB‐3 chimera. , 1994, The EMBO journal.

[16]  F. Ciardiello,et al.  AMeta-Analysis on the Interaction between HER-2 Expression and Response to EndocrineTreatment in Advanced Breast Cancer , 2005 .

[17]  Monilola A. Olayioye,et al.  The ErbB signaling network: receptor heterodimerization in development and cancer , 2000, The EMBO journal.

[18]  Kuo-Fen Lee,et al.  Rescue of the Cardiac Defect in ErbB2 Mutant Mice Reveals Essential Roles of ErbB2 in Peripheral Nervous System Development , 1999, Neuron.

[19]  N. Hynes,et al.  ErbB‐2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling , 1997, The EMBO journal.

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

[21]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[22]  N. Hynes,et al.  Memo mediates ErbB2-driven cell motility , 2004, Nature Cell Biology.

[23]  M. Mann,et al.  Temporal analysis of phosphotyrosine-dependent signaling networks by quantitative proteomics , 2004, Nature Biotechnology.

[24]  Carmen Birchmeier,et al.  ErbB2 pathways in heart and neural diseases. , 2003, Trends in cardiovascular medicine.

[25]  L. Presta,et al.  Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets , 2000, Nature Medicine.

[26]  Kuo-Fen Lee,et al.  Requirement for neuregulin receptor erbB2 in neural and cardiac development , 1995, Nature.

[27]  C. Hauser,et al.  Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. , 2005, Cancer research.

[28]  G. Hortobagyi,et al.  Enhanced sensitization to taxol-induced apoptosis by herceptin pretreatment in ErbB2-overexpressing breast cancer cells. , 2002, Cancer research.

[29]  M. Rudnicki,et al.  ErbB2 Is Required for Muscle Spindle and Myoblast Cell Survival , 2002, Molecular and Cellular Biology.

[30]  I. Ellis,et al.  Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. , 2005, Endocrine-related cancer.

[31]  M. Press,et al.  Determination of HER2 Gene Amplification by Fluorescence In situ Hybridization and Concordance with the Clinical Trials Immunohistochemical Assay in Women with Metastatic Breast Cancer Evaluated for Treatment with Trastuzumab , 2005, Breast Cancer Research and Treatment.

[32]  M. Sliwkowski,et al.  Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. , 2004, Molecular biology of the cell.

[33]  E. Holland,et al.  Postgenomic global analysis of translational control induced by oncogenic signaling , 2004, Oncogene.

[34]  F. Maurer,et al.  The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  V. Noronha,et al.  Adjuvant docetaxel for node-positive breast cancer. , 2005, The New England journal of medicine.

[36]  W. Muller,et al.  HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion. , 2004, Molecular biology of the cell.

[37]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Baselga,et al.  Mechanism of action of trastuzumab and scientific update. , 2001, Seminars in oncology.

[39]  G. Hortobagyi,et al.  Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. , 2004, Cancer cell.

[40]  A. Ullrich,et al.  Heregulin‐dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. , 1995, The EMBO journal.

[41]  Y. Lu,et al.  Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). , 2001, Journal of the National Cancer Institute.

[42]  Ming Tan,et al.  PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. , 2004, Cancer cell.

[43]  R. Cardiff,et al.  Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Hilsenbeck,et al.  Neoadjuvant trastuzumab induces apoptosis in primary breast cancers , 2005, Nature Clinical Practice Oncology.

[45]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[46]  M. Sliwkowski,et al.  Identification of a Region within the ErbB2/HER2 Intracellular Domain That Is Necessary for Ligand-independent Association* , 2002, The Journal of Biological Chemistry.

[47]  M. Mann,et al.  RNA and RNA Binding Proteins Participate in Early Stages of Cell Spreading through Spreading Initiation Centers , 2004, Cell.

[48]  M. Mann,et al.  Phosphotyrosine interactome of the ErbB-receptor kinase family , 2005, Molecular systems biology.

[49]  M. Moran,et al.  Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation , 1997, Molecular and cellular biology.

[50]  R. Fourney,et al.  Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer. , 1991, Cancer research.

[51]  M. Lemmon,et al.  The Single Transmembrane Domains of ErbB Receptors Self-associate in Cell Membranes* , 2002, The Journal of Biological Chemistry.

[52]  Jayanta Debnath,et al.  Modelling glandular epithelial cancers in three-dimensional cultures , 2005, Nature Reviews Cancer.

[53]  Dihua Yu,et al.  ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis. , 2005, Cancer research.

[54]  Andrew D. Yates,et al.  Athletics: Momentous sprint at the 2156 Olympics? , 2004, Nature.

[55]  Jie Leng,et al.  ErbB2 Is Necessary for Induction of Carcinoma Cell Invasion by Erbb Family Receptor Tyrosine Kinases , 2000, The Journal of cell biology.

[56]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[57]  D. Stern,et al.  ErbB2 is required for ductal morphogenesis of the mammary gland. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[58]  C. Hudis,et al.  Cardiac dysfunction in the trastuzumab clinical trials experience. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  R. Cardiff,et al.  Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Lyndsay N Harris,et al.  Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  Sheng-Chieh Hsu,et al.  Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. , 2005, Cancer cell.

[62]  M. Hung,et al.  Dysregulation of cellular signaling by HER2/neu in breast cancer. , 2003, Seminars in oncology.

[63]  M. C. Hu,et al.  HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. , 2000, The Journal of biological chemistry.

[64]  Leslie M. Shaw,et al.  The role of NFAT transcription factors in integrin-mediated carcinoma invasion , 2002, Nature Cell Biology.

[65]  H. Lane,et al.  The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. , 2002, Cancer research.

[66]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[67]  R. Gelber,et al.  Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[68]  Su Jie,et al.  FAK signaling is critical for ErbB-2/ErbB-3 receptor cooperation for oncogenic transformation and invasion , 2005, The Journal of cell biology.

[69]  M. Hung,et al.  HER-2/neu Blocks Tumor Necrosis Factor-induced Apoptosis via the Akt/NF-κB Pathway* , 2000, The Journal of Biological Chemistry.

[70]  M. Campiglio,et al.  Apoptosis induction by trastuzumab: possible role of the core biopsy intervention. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  R. Kumar,et al.  Heregulin regulation of urokinase plasminogen activator and its receptor: human breast epithelial cell invasion. , 2001, Cancer Research.

[72]  M. Dowsett,et al.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. , 2005, The New England journal of medicine.

[73]  K. Shen,et al.  Adjuvant Docetaxel or Vinorelbine with or without Trastuzumab for Breast Cancer , 2008 .

[74]  N. Socci,et al.  Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. , 2003, Molecular cell.

[75]  L. Cantley,et al.  Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[76]  S. Rabindran.  Antitumor activity of HER-2 inhibitors. , 2005, Cancer letters.

[77]  S. Ménard,et al.  Pilot Study of the Mechanism of Action of Preoperative Trastuzumab in Patients with Primary Operable Breast Tumors Overexpressing HER2 , 2004, Clinical Cancer Research.

[78]  N. Šestan,et al.  Neuregulin 1–erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Daniel Birnbaum,et al.  Identification and validation of an ERBB2 gene expression signature in breast cancers , 2004, Oncogene.

[80]  H. Lane,et al.  ERBB receptors and cancer: the complexity of targeted inhibitors , 2005, Nature Reviews Cancer.

[81]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[82]  Roman Rouzier,et al.  Breast Cancer Molecular Subtypes Respond Differently to Preoperative Chemotherapy , 2005, Clinical Cancer Research.

[83]  R. Finn,et al.  The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells , 1997, Oncogene.

[84]  M. Hung,et al.  Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. , 2004, Cancer cell.

[85]  Robert H Miller,et al.  The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes , 2001, The Journal of cell biology.

[86]  M. Hung,et al.  Role of erbB2 in breast cancer chemosensitivity. , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[87]  S. R. Datta,et al.  Transcription-dependent and -independent control of neuronal survival by the PI3K–Akt signaling pathway , 2001, Current Opinion in Neurobiology.

[88]  R. Kumar,et al.  The role of HER2 in angiogenesis. , 2001, Seminars in oncology.

[89]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[90]  E. Sahai,et al.  ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. , 2003, Cancer cell.

[91]  Gavin MacBeath,et al.  A quantitative protein interaction network for the ErbB receptors using protein microarrays , 2006, Nature.

[92]  Andrea Richardson,et al.  A role for the scaffolding adapter GAB2 in breast cancer , 2006, Nature Medicine.