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

Oncogene volume 28, pages 219–230 (2009)Cite this article

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 (Rbpjflox/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.

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Acknowledgements

The Rbpjflox/flox mice were kindly provided by Dr Tasuku Honjo, Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan, and the WAP-Cre mice were kindly provided by Dr Lothar Hennighausen, Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

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

    A Raafat, S Lawson, S Bargo, M Klauzinska, L Strizzi, A S Goldhar, D Salomon, B K Vonderhaar & R Callahan

  2. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    K Buono

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  1. A Raafat
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  2. S Lawson
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  3. S Bargo
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  4. M Klauzinska
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Correspondence to R Callahan.

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Raafat, A., Lawson, S., Bargo, S. et al. Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis. Oncogene 28, 219–230 (2009). https://doi.org/10.1038/onc.2008.379

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