Molecular and Cellular Pathobiology The Notch Pathway Inhibits TGFb Signaling in Breast Cancer through HEYL-Mediated Crosstalk

Acquired resistance to TGFb is a key step in the early stages of tumorigenesis. Mutations in TGFb signaling components are rare, and little is known about the development of resistance in breast cancer. On the other hand, an activated Notch pathway is known to play a substantial role in promoting breast cancer development. Here, we present evidence of crosstalk between these two pathways through HEYL. HEYL, a basic helix–loop–helix transcription factor and a direct target of Notch signaling, is specifically overexpressed in breast cancer. HEYL represses TGFb activity by binding to TGFb-activated Smads. HeyL / mice have defective mammary gland developmentwith fewer terminal end buds. On the other hand, HeyL transgenicmice show acceleratedmammary gland epithelial proliferation and 24% ofmultiparousmice developmammary gland cancer. Therefore, repression of TGFb signaling by Notch acting through HEYL may promote initiation of breast cancer. Cancer Res; 74(22);