Biology of HER2 and its importance in breast cancer.
Human epidermal growth factor receptor-2 (HER2/erbB-2) belongs to a family of four transmembrane receptors involved in signal transduction pathways that regulate cell growth and differentiation. Overexpression/amplification of HER2 is associated with malignancy and a poor prognosis in breast cancer. HER2 acts as a networking receptor that mediates signaling to cancer cells, causing them to proliferate. HER receptors exist as monomers but dimerize on ligand binding. HER ligands are bivalent growth factor molecules whose low-affinity site binds to HER2. No HER2-specific ligand has been identified but HER2 is the preferred heterodimerization partner for other HER receptors. HER2-containing heterodimers are relatively long-lived and potent. HER3 has no inherent activity and is the major and most potent dimerization partner of HER2. HER2 overexpression biases the formation of HER2-containing heterodimers, leading to enhanced responsiveness to stromal growth factors and oncogenic transformation. Removal of HER2 from the cell surface or inhibition of its intrinsic enzymatic activity may reduce oncogenicity. Our research suggests that the antitumor efficacy of HER2-specific antibodies such as Herceptin relates to their ability to direct HER2 to a Cbl- dependent endocytosis and degradation pathway. The reported clinical therapeutic efficacy of anti-HER2 monoclonal antibodies in breast cancer highlights the importance of understanding the biology of HER2.
Yarden
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Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel. yosef.yarden@weizmann.ac.il
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001940:Breast / Q000254:growth & development / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019281:Dimerization; D018450:Disease Progression; D005314:Embryonic and Fetal Development / Q000235:genetics; D004705:Endocytosis; D004847:Epithelial Cells / Q000502:physiology; D019143:Evolution, Molecular; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D008024:Ligands; D008322:Mammals / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology; D000068878:Trastuzumab; D044767:Ubiquitin-Protein Ligases
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008024:Ligands; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab; D044767:Ubiquitin-Protein Ligases; C067419:CBL protein, human; C493849:Cbl protein, mouse