ErB-2/HER2 Oncogene in Breast Cancer: Does Bivalency of Growth Factors Drive Tumorigenicity Through Receptor Heterodimerization

The HER2ErbB-2 oncogenic protein contributes to virulence of human cancer of epithelia cells, but the exact mechanism of its action is incompletely understood. We propose that ErbB-2 acts as a shared low affinity receptor for a large group of stroma-derived growth factors. In principle, we assume that the growth factors are bivalent and they recruit ErbB-2 through their low affinity sites. Evidence supporting this model has been obtained by analyzing several previously uncharacterized growth factors. In addition, mechanisms enabling enhancement of growth factor signaling by means of endocytosis and receptor degradation were uncovered. Molecular analyses of the ErbB-2 molecule by using specific antibodies and deletion mutants support direct binding of growth factors to ErbB-2 albeit with low affinity and provide initial structural data. Attempts to develop antagonists of the ErbB-2 binding sites are described.