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ErbB2 induces Notch1 activity and function in breast cancer cells

Jaime Lindsay1, Xuanmao Jiao, Toshiyuki Sakamaki

  • 1Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.

Clinical and Translational Science
|May 7, 2010
PubMed

Insights

ErbB2 oncogene in breast cancer activates Notch1 signaling. This pathway involves cyclin D1, which amplifies Notch1 activity by inhibiting Numb, promoting tumor growth.

Area of Science:

  • Molecular oncology
  • Cell signaling pathways

Background:

  • ErbB2 (Her2/neu) oncogene overexpression is common in human breast cancers.
  • Cyclin D1 is a key regulator of cell cycle progression and a downstream target of ErbB2.
  • The Notch signaling pathway plays a critical role in cell proliferation and differentiation.

Purpose of the Study:

  • To investigate the relationship between ErbB2 and Notch1 signaling in breast cancer.
  • To elucidate the role of cyclin D1 in mediating ErbB2-induced Notch1 activity.
  • To identify the molecular mechanisms by which cyclin D1 influences Notch1 activity.

Main Methods:

  • Utilized mammary epithelial cells and Foxed Notch (Notch(fl/fl)) mice models.
  • Employed genetic deletion and small interfering RNA (siRNA) to manipulate gene expression.
  • Assessed DNA synthesis, contact-independent growth, and mammosphere formation.
  • Measured Notch1 activity and Numb expression levels.

Main Results:

  • ErbB2 was demonstrated to induce Notch1 signaling pathway activity.
  • Notch1 was essential for ErbB2-induced DNA synthesis, contact-independent growth, and mammosphere formation.
  • Cyclin D1 was identified as a downstream target of Notch1, and it amplifies Notch1 activity by inhibiting Numb.

Conclusions:

  • ErbB2 promotes breast cancer growth by inducing Notch1 activity.
  • Cyclin D1 acts downstream of Notch1, amplifying its activity by repressing Numb.
  • This study reveals a novel pathway where ErbB2 induces Notch1 activity via cyclin D1 induction.

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