The HER receptor family

The HER2 gene was discovered thanks to its homology with the gene coding for the epithelial growth factor receptor (EGF). It was therefore called Human Epidermal Growth Factor Receptor type 2 (or HER-2). The HER2 gene is also called c-erbB-2. It is also referred to as HER2/neu by certain investigators because of its similarities with the neu gene from the rat.

This HER2 gene is a protooncogen implied in the synthesis of a surface protein HER-2 which is a receptor with tyrosine kinase activity. It transmits growth signals from outside to inside the cell, thus participating in the regulation of cell growth, division and differentiation.

The overexpression of the HER-2 protein is found in many types of solid tumours and is induced by the amplification of the HER2 gene. This gene amplification results more or less from the deregulation of gene control rather than from a direct mutation of the HER2 gene. The overexpression of the HER2 receptor induces its constant activity which can then lead to malignant transformation.

The family of HER genes comprises 4 very close genes which code for growth factor receptors HER1 to HER4. All these receptors have a tyrosine kinase activity stimulating cell growth. This activity is essential in the regulation of cell growth and survival as well as cell differentiation and migration. The ligands for HER1 are EGF, TGF α, amphireguline, EGF bound to heparin, and probably others. Some ligands are known for HER3 and HER4 and appear to be related to the neu-reguline family (for nerve growth). There is no known ligand for HER2.

Each HER receptor exists as a monomer in equilibrium with dimers stabilised by the ligand. Even in the absence of known ligands, HER2 is the preferential partner for constituting heterodimers: HER2 is activated by the ligand recognised by the other partner receptor . Thus HER2 participates in signal transmission without any specific ligand.

In man, amplification of the HER2 gene is observed in many tumours and stimulates their growth. These tumours, which have an increased number of HER2 receptors on their cell surface, are called HER2 positive tumours. About 30% of breast cancers are HER2 positive, and many other solid tumours are also positive.

The presence of an amplification induced overexpression of HER2 receptors is a predictive factor of poor prognosis (reduction of disease free survival and of global survival).

The extracellular accessibility of HER2 receptors makes them a good target for antitumour treatment with monoclonal antibodies.