ErbB2/HER2: Its Contribution to Basic Cancer Biology and the Development of Molecular Targeted Therapy

ErbB2, one of the receptor tyrosine kinase superfamily has attracted the attention of cancer researchers since its discovery. Thirty years ago, ErbB2 was discovered as an oncogene that transforms NIH3T3 cells. The first decade of ErbB2 research revealed that it is a member of the ErbB receptor family and is deregulated in various types of human cancer. In the second decade, one significant discovery came from the crystallography with the rational theory that explains why no ligands specific for ErbB2 have been identified so far, and the other breakthrough came from the clinical field with the appearance of ErbB-targeted therapeutics. Today, cancer researchers strive to describe the elaborate signaling network of ErbB receptors by proteomic analysis, and our knowledge of their function, which is far from complete, is being applied to develop more efficient ErbB-targeted therapeutics for cancer patients. We will begin the story of ErbB2 with its discovery as an oncogene called neu. In the dawn of oncogene research, this gene, derived from a rat tumor, was classified as one of the most pivotal genes in human cancer, along with the oncogenes Ras and Myc and the tumor suppressor gene p53. This is because ErbB2 is frequently amplified and overexpressed in certain human cancers, such as breast carcinoma. Similar to other oncogenes, subsequent research demonstrated its indispensable role in development. Now, our interest is whether ErbB2 acts on the same target proteins in cancer and in normal development. The signaling networks downstream of ErbB receptors are complex because there are various ligands for each receptor, except ErbB2, and the composition of the ErbB dimer seems to define downstream signaling targets. For example, EGFR (epidermal growth factor receptor)-containing heterodimers prefer to stimulate the mitogen-activated protein kinase (MAPK) cascade, while ErbB3-containing dimers preferably activate phosphatidylinositol 3kinase (PI3K). This characteristic is reflected in the difficulty in choosing the best therapeutics corresponding to each case in the clinic.