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

Oncogene. 2009 Jan 15;28(2):219-30. doi: 10.1038/onc.2008.379. Epub 2008 Oct 6.


Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. We have conditionally ablated the Rbpj gene in the mammary glands of mice expressing whey acidic protein (Wap)-Int3. Interestingly, Rbpj knockout mice (Wap-Cre(+)/Rbpj(-/-)/Wap-Int3) have normal mammary gland development, suggesting that the effect of endogenous Notch signaling on mammary gland development is complete by day 15 of pregnancy. RBP-J heterozygous (Wap-Cre(+)/Rbpj(-/+)/Wap-Int3) and Rbpj control (Rbpj(flox/flox)/Wap-Int3) mice are phenotypically the same as Wap-Int3 mice with respect to mammary gland development and tumorigenesis. In addition, the Wap-Cre(+)/Rbpj(-/-)/Wap-Int3-knockout mice also developed mammary tumors at a frequency similar to Rbpj heterozygous and Wap-Int3 control mice but with a slightly longer latency. Thus, the effect on mammary gland development is dependent on the interaction of the Notch ICD with the transcription repressor/activator Rbpj, and Notch-induced mammary tumor development is independent of this interaction.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma, Papillary / genetics
  • Adenocarcinoma, Papillary / pathology
  • Agar
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Transformation, Viral / genetics
  • Female
  • Homeodomain Proteins / metabolism
  • Mammary Glands, Animal / embryology*
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Tumor Virus, Mouse / genetics
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Milk Proteins / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Pregnancy
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Receptor, Notch4
  • Receptors, Notch / chemistry
  • Receptors, Notch / deficiency
  • Receptors, Notch / genetics
  • Receptors, Notch / physiology*
  • Recombinant Fusion Proteins / physiology
  • Repressor Proteins / genetics
  • Terminal Repeat Sequences / genetics
  • Transcription Factor HES-1
  • Tumor Cells, Cultured / cytology


  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Hes1 protein, mouse
  • Hey1 protein, mouse
  • Hey2 protein, mouse
  • Homeodomain Proteins
  • Milk Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Receptor, Notch4
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Transcription Factor HES-1
  • whey acidic proteins
  • Notch4 protein, mouse
  • Agar