Role of HER2/HER3 co-receptor in breast carcinogenesis.

ErbB receptors are essential mediators of cell proliferation and differentiation. Their aberrant activation is associated with the development and severity of many cancers. Homo- and heterodimerization of ErbB receptors result in a wide variety of cellular signal transduction. Dimerization of human epidermal growth-factor receptor (HER)2 and HER3 occurs frequently and is a preferred heterodimer. The HER2/HER3 dimer constitutes a high affinity co-receptor for heregulin, which is capable of potent mitogenic signaling. HER3 is a kinase-defective protein that is phosphorylated by HER2. Tyrosine phosphorylated HER3 is able to directly couple to phosphatidylinositide 3-kinase, a lipid kinase involved in the proliferation, survival, adhesion and motility of tumor cells. The authors' research provides mechanistic evidence that apigenin induces apoptosis by depleting the HER2 protein and, in turn, suppressing the signaling of the HER2/HER3-phosphatidylinositide 3-kinase/Akt pathway. This indicates that inhibition of HER2/HER3 heterodimer function may be an especially effective and unique strategy for blocking the HER2-mediated carcinogenesis of breast cancer cells.