Biochemistry of HER2 oncogenesis in breast cancer

HER2/ErbB-2 belongs to a family of four receptors that bind growth factors as dimers and transmit cellular signals. The ErbB-2 signaling unit shares functional characteristics with other modules whose function is essential for morphogenesis of epithelial organs, including the mammary gland. However, unlike other receptors, ErbB-2 binds no known growth factor ligand with high affinity, and its oncogenic potential is exceptionally high. Biochemical and genetic lines of evidence imply that ErbB-2 is a unique receptor: by serving as a preferred heterodimeric partner of the other ErbB receptors, it enhances and prolongs cell-to-cell signals. ErbB-2-containing heterodimers are long-lived and their signals are relatively potent because the rate of ligand dissociation is decelerated by ErbB-2, and their rate of endocytosis is relatively slow. Apparently, all ErbB ligands are bivalent molecules, whose low affinity site prefers ErbB-2. Hence, overexpression of ErbB-2 in epithelial tumor cells biases formation of heterodimers, leading to enhanced responsiveness to stromal growth factors and, eventually, to oncogenic transformation. Consequently, removal of ErbB-2 from the cell surface or inhibition of its intrinsic enzymatic activity may reduce oncogenicity. Indeed, anti-ErbB-2 antibodies that can effectively internalize the oncoprotein are therapeutically beneficial. We conclude that ErbB-2 developed as a master regulator of a signaling network essential for normal physiology. However, ErbB-2 opportunistically is exploited by oncogenic mechanisms. This understanding may prove useful for developing clinical strategies to inhibit ErbB-mediated cancer.