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Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis

A Raafat1, S Lawson, S Bargo

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

Oncogene
|October 7, 2008
PubMed

Insights

Notch 4 signaling in mice disrupts mammary gland development and causes tumors. Ablating Rbpj rescues development but not tumor formation, indicating distinct pathways for these Notch4 effects.

Area of Science:

  • Developmental Biology
  • Cancer Biology
  • Molecular Signaling

Background:

  • Transgenic mice expressing Notch 4 intracellular domain (Int3) exhibit mammary gland developmental arrest and tumorigenesis.
  • Notch4 signaling relies on Int3 interaction with the transcription factor Rbpj.

Purpose of the Study:

  • To investigate the role of Rbpj in Notch4-mediated mammary gland development and tumorigenesis.
  • To determine if Rbpj is essential for both phenotypes induced by Notch4 Int3.

Main Methods:

  • Conditional ablation of the Rbpj gene in mammary glands of whey acidic protein (Wap)-Int3 transgenic mice.
  • Phenotypic analysis of mammary gland development and tumor incidence in Rbpj knockout and control mice.

Main Results:

  • Rbpj knockout mice (Wap-Cre(+)/Rbpj(-/-)/Wap-Int3) displayed normal mammary gland development.
  • Mammary tumor development occurred in Rbpj knockout mice, similar to controls, but with a slightly longer latency.
  • Mammary gland development effects are dependent on Int3-Rbpj interaction, while tumor development is independent.

Conclusions:

  • The developmental effects of Notch4 Int3 in mammary glands are mediated through Rbpj.
  • Notch4-induced mammary tumorigenesis is independent of the Rbpj interaction, suggesting alternative signaling pathways.

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