Molecular Mechanisms of ErbB2-Mediated Breast Cancer Chemoresistance

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Abstract

The erbB2 (also known as HER2 or neu) gene encodes a 185-kDa transmembrane glycoprotein, which belongs to the epidermal growth factor receptor (EGFR) family. ErbB2 is a receptor tyrosine kinase with intrinsic tyrosine kinase activity. The mammalian EGFR family comprises four receptors (EGFR, ErbB2, ErbB3, and ErbB4), which are derived from a series of gene duplications early in vertebrate evolution and are 40%–45% identical.1 ErbB2 is the only EGFR family member for which no ligand has been found. This may be explained by the unique structure of the ErbB2 extracellular domain, which is not favorable for ligand binding.2,3 Since ErbB2 extracellular domain is always in the open conformation, ErbB2 is the preferred binding partner of all ErbB receptors even as a monomer.24 The binding of ErbB2 to other ErbB receptors results in increased signaling potency of the dimerized receptors through several means, including increased ligand affinity, increased coupling efficiency to signaling molecules, and decreased rate of receptor internalization.58