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

The hypothesis that an overexpressed ErbB-2 can transform epithelial cells by enhancing binding of many stromal ligands has been tested with neuregulins. Neuregulins and other epidermal growth factor EGF- like ligands exert their pleiotropic effects and oncogenic signals through four ErbB receptor tyrosine kinases capable of generating homo- and hetero- dimeric combinations. Ligand-induced dimerization of ErbB proteins is driven by the apparent bivalence of EGF-like molecules. In the case of neuregulin-1 the two putative receptor-binding sites localize, in part, to the two termini of the EGF-like motif. We show that chemical coupling of the two sites can reconstitute bio-activity. The short synthetic ligand, but not derivative peptides, specifically activated the most transforming receptor heterodimer, namely a combination of ErbB-2, a ligand-less oncogenic receptor, and ErbB-3, a kinase-defective receptor. No other ErbB combination, including those containing ErbB-4, underwent stimulation. Although its binding affinity was compromised, the analog, like neuregulins, stimulated receptor phosphorylation, intracellular signaling, and proliferation of cells. These results imply that miniaturization of neuregulins and their precise targeting to specific ErbB combinations are feasible. Within the framework of the IDEA research, this last line of evidence joins the previously reported findings in collectively supporting a bivalent mode of ligand-ErbB interactions.