The Notch pathway inhibits TGFβ signaling in breast cancer through HEYL-mediated crosstalk

Liangfeng Han, Adam Diehl, Nguyen K. Nguyen, Preethi Korangath, Weiwen Teo, Soonweng Cho, Scott Kominsky, David L. Huso, Lionel Feigenbaum, Alan Rein, Pedram Argani, Goran Landberg, Manfred Gessler, Saraswati Sukumar

Research output: Contribution to journalArticlepeer-review

Abstract

Acquired resistance to TGFβ is a key step in the early stages of tumorigenesis. Mutations in TGFβ 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 TGFβ activity by binding to TGFβ-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 TGFβ signaling by Notch acting through HEYL may promote initiation of breast cancer.

Original languageEnglish (US)
Pages (from-to)6509-6518
Number of pages10
JournalCancer Research
Volume74
Issue number22
DOIs
StatePublished - Nov 15 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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