Abstract 2841: Inducible modulation of NF-kappaB in macrophages reveals that timing of intervention may be critical to therapeutic outcome during mammary tumorigenesis

Abstract

Abstract Elevated levels of NF-kappaB signaling are associated with multiple cancers. Therefore, it is not surprising that inhibitors of NF-kappaB are being investigated as potential therapeutics. While extensive efforts are being made to identify inhibitors there is less focus on investigating the effects of inhibition in specific cell types and during defined stages of tumor progression. We have developed murine transgenic models that enable us to induce expression of an activator or inhibitor of NF-kappaB in macrophages, by adding doxycycline to the drinking water of mice. We have combined these with the Polyoma model of mammary cancer to investigate the effects of modulation of NF-kappaB signaling specifically within macrophages. Given several recent publications we were predicting that activation of NF-kappaB would have pro-tumor effects. However, using a tail vein injection model, our data identifies a stage during progression in which activation of NF-kappaB in macrophages significantly limits metastasis. Activation of NF-kappaB alters immune cell populations and results in rapid killing of tumor cells during the seeding phase. In this model inhibition of NF-kappaB in macrophages during this critical stage of metastasis is pro-tumor. This suggests that while inhibition of NF-kappaB at later stages of tumor progression may have therapeutic benefit, inhibition during the seeding phase my lead to the opposite effect. Our studies highlight the importance of continued investigation into aspects of cell specificity and timing that may change the potential outcome of a clinical trial using NF-kappaB inhibitors. 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 2841. doi:10.1158/1538-7445.AM2011-2841