Abstract
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
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Research Support, N.I.H., Intramural
MeSH terms
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Adenocarcinoma, Papillary / genetics
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Adenocarcinoma, Papillary / pathology
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Agar
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Cycle Proteins / metabolism
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Cell Transformation, Viral / genetics
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Female
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Homeodomain Proteins / metabolism
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Mammary Glands, Animal / embryology*
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Mammary Neoplasms, Experimental / genetics*
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Mammary Neoplasms, Experimental / pathology
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Mammary Tumor Virus, Mouse / genetics
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Mice
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Mice, Knockout
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Mice, Nude
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Milk Proteins / genetics
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Pregnancy
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Receptor, Notch4
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Receptors, Notch / chemistry
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Receptors, Notch / deficiency
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Receptors, Notch / genetics
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Receptors, Notch / physiology*
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Recombinant Fusion Proteins / physiology
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Repressor Proteins / genetics
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Terminal Repeat Sequences / genetics
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Transcription Factor HES-1
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Tumor Cells, Cultured / cytology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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Hes1 protein, mouse
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Hey1 protein, mouse
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Hey2 protein, mouse
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Homeodomain Proteins
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Milk Proteins
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Receptor, Notch4
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Receptors, Notch
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Recombinant Fusion Proteins
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Repressor Proteins
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Transcription Factor HES-1
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whey acidic proteins
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Notch4 protein, mouse
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Agar