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Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis

Suruchi Mittal1, Deepa Subramanyam, Devaveena Dey

  • 1Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560 012, Karnataka, India. suruchi.mittal@gmail.com

Molecular Cancer
|December 25, 2009
PubMed
Abstract

Insights

Notch signaling is frequently activated in breast cancers and early precursors, suggesting a key role in disease development. Combined inhibition of Notch and Ras/MAPK pathways may offer a new breast cancer treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Aberrant Notch signaling is implicated in breast cancer development.
  • The precise role and mechanism of Notch pathway activation in breast cancer remain unclear.
  • Detailed expression analysis of Notch pathway components is needed to understand its function in breast cancer progression.

Purpose of the Study:

  • To analyze the expression of Notch receptors, ligands, and downstream targets in breast cancer.
  • To investigate the activation status of the Notch pathway during breast cancer progression.
  • To elucidate the mechanism of Notch pathway action and its cooperation with other signaling pathways in breast cancer.

Main Methods:

  • Quantitative analysis of Notch receptors (Notch 1-4), ligands (Jagged1, Jagged2, Delta-like 1, 4), and downstream targets (Hes1/Hes5) expression in breast cancer tissues.
  • Detection of active, cleaved Notch1 and phosphorylated Erk1/2 (p-Erk1/2) using immunohistochemistry.
  • In vitro transformation assays using immortalized breast cells with constitutively active Notch1 and Ras/MAPK pathway components.

Main Results:

  • Increased expression of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers.
  • Aberrant Notch pathway activation, indicated by cleaved Notch1 and Hes1/5, detected in approximately 75% of breast cancers and early precursors.
  • Notch1 cooperates with the Ras/MAPK pathway to mediate cell transformation, with Notch-Ras cooperation linked to high lymph node positivity in tumors.

Conclusions:

  • Increased Notch receptor and ligand expression and pathway activation in breast cancer and its precursors highlight Notch signaling's critical role in pathogenesis.
  • Notch pathway cooperation with Ras/MAPK in transformation suggests combined inhibition as a potential therapeutic strategy for breast cancer.

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