Signaling Pathways in the Normal and Neoplastic Breast

This chapter examines the signaling pathways in the normal and neoplastic breast. The epidermal growth factor (EGF) family members that bind to EGFR are EGF, transforming growth factor α (TGFα), amphiregulin (AR, a heparin-binding factor), heparin-binding EGF (HbEGF), epiregulin, and β-cellulin. Cripto (CR-1) is an EGF family member that plays an important role in embryogenesis and mammary gland development. CR-1 is overexpressed in several human tumors. However, CR-1 binds to a type I serine/threonine kinase receptor for activin (ALK4), which is expressed on the cell surface of mammary epithelial cells, rather than binding to EGFR or one of the other ErbB receptors. ErbB receptors undergo homo- or heterodimerization following ligand binding. After ligand binding, EGFR/ErbB1/HER-1 undergoes either endocytosis and degradation by both proteasomal and lysosomal pathways, or the receptor is recycled to plasma membrane. ErbB2/HER-2 is considered to be endocytosis-impaired, and is the most stable protein among ErbBs in the plasma membrane. Ductal growth in the mammary epithelium is defective when ErbB2 is disrupted in the mammary gland, implying a prominent role for ErbB2 in mammary ductal growth. ErbB2 plays a significant role in ductal morphogenesis. While kinase-dead, ErbB3/HER-3 frequently forms a high-affinity co-receptor for heregulin by heterodimerization with ErbB2/HER-2. ErbB3/HER-3 possesses several docking sites for PI3K, and can initiate PI3K/Akt signaling when transactivated by ErbB2/HER-2. EGF can act as an oncogene-like molecule when transfected and overexpressed in immortalized rodent fibroblasts. Forced overexpression of EGFR in the mammary gland, under the control of the MMTV or β-lactoglobulin (BLG) promoters, results in abnormal mammary gland development and the production of epithelial hyperplasias.