The Notch pathway inhibits TGF? signaling in breast cancer through HEYL-mediated crosstalk.

ABSTRACT: Acquired resistance to TGF? is a key step in the early stages of tumorigenesis. Mutations in TGF? 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 TGF? activity by binding to TGF?-activated Smads. HeyL(-/-) mice have defective mammary gland development with fewer terminal end buds. On the other hand, HeyL transgenic mice show accelerated mammary gland epithelial proliferation and 24% of multiparous mice develop mammary gland cancer. Therefore, repression of TGF? signaling by Notch acting through HEYL may promote initiation of breast cancer.

SUBMITTER: Han L 

PROVIDER: S-EPMC4233182 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature