Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: 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. Interestingly, Rbpj knockout mice (Wap-Cre+/Rbpj-/-/Wap-Int3) have normal mammary gland development also developed mammary tumors with a slightly longer latency than the Wap-Int3 mice. Thus, Notch-induced mammary tumor development is independent of this interaction. Here, we show that Int3 activates NF-κB in HC-11 cells and induces p50 Phosphorylation in absence of Rbpj. Also, Int3 regulates NF-κB in mammary tumors via IKK-mediated pathway. Treatment of Wap-Int3 baring tumors mice with IKK inhibitor resulted in tumors regression. Also, Wap-Int3/p50 knockout mice did not develop mammary tumors. The data indicates that the NF-κB canonical pathway is the Int3-Rbpj independent pathway.

Citation Format: Ahmed M. Raafat, Sharon Bargo, Robert Callahan. Activation of NF- KB by Notch4/Int3 is Rbpj-independant. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5180. doi:10.1158/1538-7445.AM2013-5180

©2013 American Association for Cancer Research
2013