I. the Importance of Her2 in Breast Cancer

The human epidermal growth factor receptors (HER), also known as ERBB receptors, are a family of signal transduction proteins. There are 4 family members in humans—HER1, HER2, HER3, and HER4—each of which is composed of an extracellular (ligandbinding) domain, a transmembrane domain, and an intracellular tyrosine kinase, except for HER3, which lacks a tyrosine kinase domain (Figure 1). HER-family receptors become active upon interaction with ligand and subsequent dimerization, followed by activation of downstream signaling proteins by phosphorylation. In humans, the 4 HER proteins interact with a range of ligands, although HER2 has no known activating ligands. For example, HER1 interacts with at least 6 ligands: epidermal growth factor (EGF), transforming growth factor (TGF ), amphiregulin, heparin-binding EGF-like growth factor, betacellulin, and epiregulin. HER2, also referred to as ERBB2, NEU, or HER2/neu, can act as a dimerization partner with the other HER receptor proteins. As there are no known activating ligands for HER2, its activity is a consequence of its dimerization with other HER-family receptors as well as its homodimerization. Upon activation, the tyrosine kinase domain of each of the HER-family receptors can activate downstream signaling molecules, such as those in the PI3K/Akt and RAS/RAF/MEK/MAPK pathways.