4 HER-2 Signaling in Human Breast Cancer Kathleen M. Woods Ignatoski University of Michigan, USA 1. Introduction 1.1 erbB family HER-2 is a member of the erbB family of receptor tyrosine kinases. Epidermal Growth Factor Receptor (EGFR) was first identified as the cellular homolog of the transduced oncogene of the avian retroviruses such as avian ERythroBlastosis virus, which causes erythroleukemia and fibrosarcoma and gives rise to the family name (erbB). EGFR, as its name implies, was shown by Stanley Cohen to induce the growth of epidermal cells (Todaro, DeLarco et al. 1976). The EGFR family consists of four members: erbB-1 (EGFR), erbB-2 (HER-2/neu), erbB-3 (HER-3), and erbB-4 (HER-4). Her-1, -2, and -3 have been associated with tumorigenesis (Suo, Emilsen et al. 1998). HER-4 has been implicated in development and tumor suppression, possibly by sequestration of the other erbB receptors in dimers. Ligand binding stabilizes dimer formation, leading to intracellular signaling. Each receptor consists of an extracellular domain that contains the ligand binding sites, an intracellular domain that contains the tyrosine kinase activity, and a cytoplasmic tail that is involved in cellular signaling. EGFR can be stimulated by an array of ligands, including EGF, transforming growth factor α (TGF-α), heparin-binding EGF (HB-EGF), and heregulins. HER-3 can bind heregulins (Holmes, Sliwkowski et al. 1992); although, it in and of itself does not have an active kinase domain. Heregulin binding to HER-3 facilitates dimerization with other erbB receptors which promote the phosphorylation of HER-3 and subsequent activation of downstream signals. HER-2 does not have any known ligands; however, several intriguing papers have been published recently on this topic. The Calloway group has had a series of papers (Carraway, Carvajal et al. 1993; Carraway and Cantley 1994; Carraway, Sliwkowski et al. 1994; Carraway, Rossi et al. 1999; Komatsu, Jepson et al. 2001; Carraway and Carraway 2007; Kozloski, Carraway et al. 2010) showing that the extracellular domain of HER-2 can bind the intramembrane protein MUC4, suggesting that MUC4 was the ligand for HER-2. MUC4 appears to play a role in mammary gland development at the lactation step along with HER- 2. In cancer, MUC 4 blocks apoptosis and stabilizes HER-2/HER-3 dimers. In normal epithelia, MUC 4 sequesters HER-2 to the apical surface, separating it from HER-3, which is on the lateral surface (Carraway and Carraway 2007). These data make a compelling argument for MUC4 as a ligand for HER-2. More recently, Day, et al. (Najy, Day et al. 2008) showed that the extracellular domain of E- cadherin could activate HER-2 and EGFR. They have shown that the extracellular domain of E-cadherin is cleaved by the ADAM proteases. Since E-cadherin is normally present on