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Related Experiment Videos

Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis.

A Raafat1, A Zoltan-Jones, L Strizzi

  • 1Oncogenetics Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Oncogene
|August 1, 2006
PubMed
Summary

Notch4 Int3 overexpression drives mammary tumors in mice. Treatment with Gleevec, a tyrosine kinase inhibitor, reduced tumor growth by targeting c-Kit and PDGFR-alpha, suggesting their oncogenic role in Notch4-induced tumorigenesis.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Overexpression of the Notch4 intracellular domain (Int3) in transgenic mice leads to mammary tumor development.
  • Microarray analysis of these tumors revealed elevated c-Kit expression, suggesting a role for tyrosine kinases.

Purpose of the Study:

  • To investigate the role of tyrosine kinase receptor activity in Int3-induced mammary tumorigenesis.
  • To evaluate the efficacy of Gleevec, a tyrosine kinase inhibitor, in treating Int3-driven mammary tumors.

Main Methods:

  • Treatment of WAP-Int3 tumor-bearing mice with Gleevec via Alzet pumps.
  • Analysis of c-Kit, PDGFRs, and c-Abl phosphorylation.
  • Assessment of cell proliferation, angiogenesis, and apoptosis.
  • ব্যবহার of small interfering RNA (siRNA) to knock down c-Kit, PDGFRs, and c-Abl in HC11 cells overexpressing Int3.

Related Experiment Videos

  • Soft agar colony formation assays.

    • Main Results:

    • Gleevec treatment inhibited phosphorylation of c-Kit, PDGFRs, and c-Abl in Int3 transgenic mammary tumors.
    • Gleevec treatment led to decreased cell proliferation and angiogenesis, and increased apoptosis.
    • Knockdown of c-Kit and/or PDGFR-alpha using siRNA inhibited colony formation in soft agar for HC11-Int3 cells.

    Conclusions:

    • Gleevec effectively inhibits Int3-induced transformation of mammary cells and tumor development.
    • c-Kit and PDGFR-alpha tyrosine kinases play an oncogenic role in Notch4/Int3 signaling pathways.
    • Targeting these tyrosine kinases represents a potential therapeutic strategy for Int3-driven mammary tumors.