ERBB Signaling Pathway in Cancer Stem Cells

The epidermal growth factor receptor (EGFR) was first tyrosine kinase receptor linked to human cancers. EGFR or ERBB1 is a member of ERBB subfamily, which consists of four type I transmembrane receptor tyrosine kinases, ERBB1, 2, 3 and 4. ERBBs form homo/heterodimers after ligand binding except ERBB2 and consequently becomes activated. Different signal pathways, such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), RAS/RAF/MEK/ERK, phospholipase Cγ and JAK-STAT, are triggered by ERBB activation. Since ERBBs, through these pathways, regulate stemness and differentiation of cancer stem cells (CSCs), their roles in CSC tumorigenicity have extensively been investigated. The hyperactivation of ERBBs and its downstream pathways stimulated by either genetic and/or epigenetic factors are frequently described in many types of human cancers. Their dysregulations make cells acquiring CSC characters such as survival, tumorigenicity and stemness. Because of the roles in tumor growth and progress, ERBBs are considered to be one of the drug targets as cancer treatment strategy. In this chapter, we will summarize the structure, function and roles of ERBB subfamily along with their relative pathways regulating the stemness and tumorigenicity of CSCs. Finally, we will discuss the targeting therapy strategies of cancer along with ERBBs in addition to some challenges and future perspectives.