Dysregulation of cellular signaling by HER2/neu in breast cancer

https://doi.org/10.1053/j.seminoncol.2003.08.006Get rights and content

Abstract

Human epidermal growth factor receptor-2 (HER2/neu; erbB2) belongs to a family of four transmembrane receptor tyrosine kinases involved in signal transduction pathways that regulate cell growth and proliferation. Amplification or overexpression of HER2/neu occurs in about 30% of human breast and ovarian cancers and is associated with a poor clinical outcome, including short survival time and short time to relapse. Recent advances in our understanding of HER2/neu signaling pathways have greatly increased our knowledge of breast cancer tumorigenesis and have provided new targets for treating breast and ovarian tumors that overexpress HER2/neu. This review will focus on the signaling network mediated by HER2/neu in breast cancer and discuss our understanding of these pathways, which seem to be particularly important in mediating cell survival and growth under a wide variety of circumstances in breast cancer.

Section snippets

HER2/neu disrupts cell-cycle regulation

In eukaryotes, cell-cycle transitions are carefully orchestrated by the ordered assembly and activation of several conserved cyclin-dependent kinase (CDK) complexes. Cyclin-dependent kinase function is regulated by the levels of cyclin, the formation of cyclin-CDK complexes, the phosphorylation of CDK kinase, the subcellular localization of cyclin-CDK complexes, and by two families of cell-cycle inhibitory proteins (known as CDK inhibitors).10 Thus, the cyclin-CDK complexes are the ultimate

HER2/neu disrupts the tumor suppressor p53-MDM2-ARF pathway

The p53 tumor suppressor protein regulates the response of mammalian cells to stress and damage through the transcriptional activation of genes involved in cell-cycle control and apoptosis. Disruption of any of these processes can allow cells to escape growth constraints and apoptosis, and permit the passage of mutations from one generation to the next.23, 24, 25, 26, 27, 28, 29 Evidence for the tumor suppressor function of p53 comes from studies showing that tumors develop with a high

Wnt signaling and HER2/neu induce mammary tumorigenesis via β-cantenin

β-catenin, a member of the armadillo repeat protein family, plays a pivotal role in cell adhesion and Wnt signaling.50 In adherent junctions of cell-cell contacts, β-catenin bridges directly between the cytoplasmic domain of E-cadherin and the actin cytoskeleton through its interaction with β-catenin. In Wnt signaling, binding of soluble Wnt ligands to the Frizzled receptor results in the inactivation of GSK-3β, which normally phosphorylates β-catenin and regulates its ubiquitination and

NF-κB pathways in breast cancer

The NF-κB family of transcription factors consists of p65 (RelA), p50, c-Rel, RelB, and p52 subunits, which can dimerize in various combinations and are activated by a variety of stimuli, including cytokines and oncoproteins. Transient activation of NF-κB in response to the stimulation of cytokines occurs as an inflammatory response; however, sustained activation of NF-κB has been implicated in the pathogenesis of cancer and autoimmune disease.61, 62 In unstimulated cells, the majority of NF-κB

HER2/neu is a potential antitumor target

Breast cancer is a heterogeneous disease with different mutations in either tumor suppressor genes or oncogenes. The effectiveness of the treatment of breast cancer depends on the early diagnosis and quality of classification of the disease that is used to predict the patient’s response to various therapies. With the advance of microarray methods to analyze DNA, RNA, and proteins from breast cancer samples, new methods have developed to refine the early diagnosis and classification of breast

References (107)

  • T. Caspari

    How to activate p53

    Curr Biol

    (2000)
  • J. Momand et al.

    MDM2 - Master regulator of the p53 tumor suppressor protein

    Gene

    (2000)
  • S.R. Grossman et al.

    p300/MDM2 complexes participate in MDM2- mediated p53 degradation

    Mol Cell

    (1998)
  • J. Pomerantz et al.

    The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53

    Cell

    (1998)
  • Y. Zhang et al.

    ARF promotes MDM2 degradation and stabilizes p53ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways

    Cell

    (1998)
  • Y. Zhang et al.

    Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53

    Mol Cell

    (1999)
  • P. Sabbatini et al.

    Phosphoinositide 3-OH kinase (PI3K) and PKB/Akt delay the onset of p53-mediated, transcriptionally dependent apoptosis

    J Biol Chem

    (1999)
  • B.P. Zhou et al.

    HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway

    J Biol Chem

    (2000)
  • Y. Ogawara et al.

    Akt enhances Mdm2-mediated ubiquitination and degradation of p53

    J Biol Chem

    (2002)
  • L. Simpson et al.

    PTENLife as a tumor suppressor

    Exp Cell Res

    (2001)
  • L.D. Mayo et al.

    PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy

    J Biol Chem

    (2002)
  • V. Stambolic et al.

    Regulation of PTEN transcription by p53

    Mol Cell

    (2001)
  • P. Polakis

    The oncogenic activation of beta-catenin

    Curr Opin Genet Dev

    (1999)
  • H. Lickert et al.

    Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion

    J Biol Chem

    (2000)
  • J.A. Schroeder et al.

    ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV), Wnt-1 and MMTV-c-Neu transgenic carcinomas

    J Biol Chem

    (2002)
  • M.W. Mayo et al.

    The transcription factor NF-kappaBControl of oncogenesis and cancer therapy resistance

    Biochim Biophys Acta

    (2000)
  • Y. Cao et al.

    IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development

    Cell

    (2001)
  • L.V. Madrid et al.

    Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38

    J Biol Chem

    (2001)
  • M.W. Mayo et al.

    PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit

    J Biol Chem

    (2002)
  • G. Levkowitz et al.

    Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1

    Mol Cell

    (1999)
  • G. Levkowitz et al.

    c-Cbl is a suppressor of the neu oncogene

    J Biol Chem

    (2000)
  • S.A. Ettenberg et al.

    Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex

    J Biol Chem

    (2001)
  • D.B. Agus et al.

    Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth

    Cancer Cell

    (2002)
  • R. Shao et al.

    Inhibition of nuclear factor-kappaB activity is involved in E1A-mediated sensitization of radiation-induced apoptosis

    J Biol Chem

    (1997)
  • R. Shao et al.

    E1A sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of IkappaB kinases and nuclear factor kappaB activities

    J Biol Chem

    (1999)
  • Y. Yarden et al.

    Untangling the ErbB signalling network

    Nat Rev Mol Cell Biol

    (2001)
  • D. Yu et al.

    Overexpression of ErbB2 in cancer and ErbB2-targeting strategies

    Oncogene

    (2000)
  • K.L. Carraway et al.

    Neuregulin-2, a new ligand of ErbB3/ErbB4- receptor tyrosine kinases

    Nature

    (1997)
  • D.J. Slamon et al.

    Human breast cancerCorrelation of relapse and survival with amplification of the HER-2/neu oncogene

    Science

    (1987)
  • D.J. Slamon et al.

    Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

    Science

    (1989)
  • P.M. Schneider et al.

    Differential expression of the c-erbB-2 gene in human small cell and non-small cell lung cancer

    Cancer Res

    (1989)
  • D.B. Weiner et al.

    Expression of the neu gene-encoded protein (P185neu) in human non-small cell carcinomas of the lung

    Cancer Res

    (1990)
  • J. Yokota et al.

    Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue

    Oncogene

    (1988)
  • C.J. Sherr et al.

    Inhibitors of mammalian G1 cyclin-dependent kinases

    Genes Dev

    (1995)
  • J.W. Harper et al.

    The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases

    Cell

    (1993)
  • M. Asada et al.

    Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation

    EMBO J

    (1999)
  • J. Chen et al.

    Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA

    Nature

    (1995)
  • B.P. Zhou et al.

    Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells

    Nat Cell Biol

    (2001)
  • A.E. Lenferink et al.

    ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways

    Cancer Res

    (2001)
  • L. Newman et al.

    Correlation of p27 protein expression with HER-2/neu expression in breast cancer

    Mol Carcinog

    (2001)
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    Supported by National Institutes of Health grant nos. CA 58880, CA 77858, and CA 78633; by a SPORE grant in ovarian cancer (CA 83639) (M.-C. H.); and by the Nellie Connally Breast Cancer Research Fund at The University of Texas M. D. Anderson Cancer Center (M.-C. H.).

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