Abstract 1240: Characterization of Notch3 in senescence regulation and tumor suppression

Abstract Notch signaling has been shown to regulate a broad spectrum of cell fate decisions and differentiation. However, very little is known about the role of Notch signaling in cellular senescence. Here we report that the level of Notch3, a member of Notch transmembrane receptors, is specifically elevated in human fibroblasts during senescence induced by different senescence stimuli. This up-regulation of Notch3 is required for the induction of p21 in senescent cells, whereas adventitious expression of Notch3 in early passage fibroblasts induces senescence accompanied by p21 elevation. Furthermore, we find that Notch3-mediated senescence requires a canonic Notch singling, and deletion of p21 can partially abolish Notch3-induced senescence. The expression of Notch3 is undetectable in a number of human cancer cell lines, and restored expression of Notch3 in these cancer cell lines with undetectable level of Notch3 leads to proliferative arrest. Interestingly, the expression of Notch3 in the luminal subtype of human breast cancer is significantly decreased as compared to other subtypes of breast cancer. More importantly, low level of Notch3 expression in patients with luminal type of breast cancer correlates significantly with poor clinical prognosis. Our results reveal a novel function of Notch3 in senescence regulation and tumor suppression, suggesting that modulation of Notch3 provides a potential therapeutic approach for luminal subtype of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1240. doi:10.1158/1538-7445.AM2011-1240