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Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells

Olivier Meurette1, Spyros Stylianou, Rebecca Rock

  • 1Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom. olivier.meurette@manchester.ac.uk

Cancer Research
|June 4, 2009
PubMed

Insights

Notch pathway activation in breast cancer promotes cell survival by activating Akt, which prevents apoptosis. Inhibiting Notch signaling reduces Akt activity, increasing cancer cell sensitivity to apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Aberrant Notch pathway activation is common in breast cancer, maintaining tumor cell survival.
  • Notch signaling prevents apoptosis, but the underlying mechanism is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which Notch signaling suppresses apoptosis in breast epithelial cells.
  • To investigate the role of Akt signaling in Notch-mediated cytoprotection.

Main Methods:

  • Utilized the MCF10A nontransformed breast epithelial cell line and human breast cancer cells.
  • Investigated Notch signaling, Akt activation, and apoptosis.
  • Examined the role of ASK1 and c-Jun NH(2)-terminal kinase (JNK) in the pathway.

Main Results:

  • Notch signaling induces an autocrine loop activating Akt in breast epithelial cells.
  • Akt activation is essential for Notch-mediated apoptosis protection in MCF10A cells.
  • Inhibition of Notch signaling in breast cancer cells decreased Akt activity and increased apoptosis sensitivity.
  • Akt-mediated inhibition of ASK1 prevented JNK-mediated p53 activation, conferring resistance to DNA damage-induced apoptosis.

Conclusions:

  • Notch signaling promotes breast cancer cell survival through an Akt-dependent pathway.
  • Targeting the Notch-Akt axis may represent a therapeutic strategy for breast cancer by enhancing apoptosis.

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