Fig. 8

Working model to explain increased tumor initiation and morphological changes in AREG^−/− tumors. (a) In mammary duct in absence of PyMT (top), myoepithelial cells (green) form continuous layer around luminal epithelial cells. In mature duct termini, myoepithelial layer is discontinuous. Luminal epithelial cells secrete AREG that binds to EGFR on stromal cells (yellow). Stimulated stromal cells produce FGFR ligands that bind to FGFR luminal epithelial cells and myoepithelial cells [31, 56]. In absence of AREG (bottom), EGFR/FGFR paracrine loop is interrupted and impairs proper mammary ductal development. (b) In AREG^+/+ PyMT animals (top), PyMT initiates transformation of luminal epithelial cells in mature duct termini where there are fewer myoepithelial cells. Myoepithelial cells as well as secreted growth factors such as AREG and bFGF suppress PyMT expression in mammary duct. In AREG^−/− PyMT mice (bottom), PyMT expression is more widespread. Due to global reduction in myoepithelial cells and reduced AREG and FGF expression, oncogenic transformation takes place more broadly in ductal tree. AREG amphiregulin, FGF basic fibroblast growth factor, PYMT polyoma middle-T antigen