Role of the Int-3 Oncogene in Mammary Gland Development and Tumorigenesis

Elongation and branching of epithelial ducts is a crucial event during the development of the mammary gland. Branching morphogenesis of the mouse mammary epithelial TAC-2 cell line was used as an assay to examine the role of Wnts, HGF, TGF-% and the Notch receptors in branching morphogenesis. Wnt-l was found to induce the elongation and branching of epithelial tubules, like HUF and TGF-%2, and to strongly cooperate with either HGF or TGF-%2 in this activity. The Notch4(int-3) mammary oncoprotein, an activated form of the Notch4 receptor, inhibited the branching morphogenesis normally induced by HOF and TGF-%. The minimal domain within the Notch4(int-3) protein required to inhibit morphogenesis consists of the CBF-1 interaction domain and the cdc 10 repeat domain. Co-expression of Wnt- 1 and Notch4(int-3) demonstrates that Wnt- 1 can overcome the Notch-mediated inhibition of ductal morphogenesis. These data suggest that Wnt and Notch signaling may play opposite roles in mammary gland development, a finding consistent with the convergence of the wingless and Notch signaling pathways found in Drosophila.