Molecular Basis of HER-2-Positive Breast Cancer

  • The human epidermal receptor (HER) or erbB proteins:
    • Are members of the subclass I of the receptor tyrosine kinase superfamily
      • This group contains four members:
        • Epidermal growth factor receptor (EGFR) / erbB1 / HER-1
        • erbB2 / HER-2 / neu
        • erbB3 / HER-3
        • erbB4 / HER-4
      • These proteins are made up of an:
        • Extracellular ligand-binding domain
        • A membrane-spanning region
        • A cytoplasmic domain with tyrosine kinase activity
      • Ligand binding to these receptors:
        • Leads to their homodimerizartion or heterodimerization:
          • Which promotes signal transduction
      • To date, no ligands have been identified for the HER-2 receptor:
        • However, the HER-2 receptor has been shown to be the preferred heterodimerization for other HER family members
The HER gene family. The proteins are made up of an extracellular ligand-binding domain, a membrane-sparing region, and a cytoplasmic domain with tyrosine kinase activity.
Note that HER-2 has no known ligands. Also note that HER-3 has no intrinsic tyrosine kinase activity.
  • HER-2 has been shown to be one of the most important oncogenes in human breast cancer
  • HER-2 complexes initiate intracellular signaling via the:
    • Mitogen-activated protein kinase (MAPK)
    • Phosphatidylinositol 3-kinase (PI3K) pathway
    • Phospholipase C pathway
  • In breast cell lines and model tumor systems:
    • Overexpression of the gene has been shown to be associated with:
      • Increased mitogenesis
      • Malignant transformation
      • Increased cell motility
      • Invasion
      • Metastasis
  • In human breast cancer:
    • Amplification of the gene is found in around 15% to 30% of primary invasive breast tumors:
      • In these cases, up to 100 copies have been demonstrated per cell:
        • Which is equivalent to a 50-fold increase in gene copy number per cell
      • As a result, the number of receptors per cell is increased up to 2 million
      • Overexpression at the messenger RNA or protein level:
        • Occurs in around 15% to 30% of patients with early-stage breast cancer

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