Indeed, as an orphan receptor, HER2 does not bind directly to any EGF-like ligand and its activation results from either its heterodimerization, with ligand-activated EGFR or ERBB3, or from homodimerization in the case of high concentrations of the receptor (such as when overexpressed in cancer cells) [4,46]. This evidence concerns the gene ERBB3 and cancer.