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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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The Notch pathway inhibits TGFβ signaling in breast cancer through HEYL-mediated crosstalk

Liangfeng Han1, Adam Diehl1, Nguyen K Nguyen1

  • 1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Cancer Research
|September 14, 2014
PubMed

Insights

Notch signaling, through HEYL, represses Transforming Growth Factor beta (TGFβ) activity. This crosstalk in breast cancer may drive tumorigenesis by overcoming TGFβ-mediated growth inhibition, promoting tumor initiation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Developmental Biology

Background:

  • Acquired resistance to Transforming Growth Factor beta (TGFβ) signaling is crucial in early tumorigenesis, particularly in breast cancer.
  • While mutations in TGFβ pathway components are infrequent, the mechanisms of resistance remain largely unexplored.
  • An activated Notch pathway is recognized for its role in promoting breast cancer development.

Purpose of the Study:

  • To investigate the crosstalk between Notch and TGFβ signaling pathways in breast cancer.
  • To elucidate the role of HEYL, a direct target of Notch signaling, in mediating this interaction.
  • To understand how HEYL influences TGFβ activity and mammary gland development.

Main Methods:

  • Analysis of HEYL expression in breast cancer.
  • Investigating HEYL's mechanism of repressing TGFβ activity by interacting with Smads.
  • Phenotypic analysis of mammary gland development in HeyL knockout and transgenic mouse models.

Main Results:

  • HEYL is overexpressed in breast cancer and acts as a direct target of Notch signaling.
  • HEYL represses TGFβ signaling by binding to TGFβ-activated Smads.
  • HeyL knockout mice exhibit impaired mammary gland development.
  • HeyL transgenic mice display accelerated mammary epithelial proliferation, with a significant incidence of mammary cancer in multiparous individuals.

Conclusions:

  • Notch signaling, via HEYL, represses TGFβ activity, suggesting a novel mechanism for resistance to TGFβ.
  • The Notch-HEYL-TGFβ axis plays a critical role in promoting mammary gland epithelial proliferation and may contribute to breast cancer initiation.

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