Abstract 1352: Macrophage specific regulation reveals both pro- and anti-tumor effects of NF-kappaB during mammary tumor progression

Abstract

Abstract An increased level of macrophages in human tumors is associated with a poorer prognosis. The transcription factor Nuclear Factor-kappaB (NF-kappaB) is an important regulator of gene expression within macrophages. Recent studies point to a pro-tumorigenic role for NF-kappaB activity in macrophages; however NF-kappaB also regulates expression of genes such as inducible nitric oxide synthase which are associated with anti-tumor effects. We believe that NF-kappaB activity in macrophages can have both anti- and pro-tumor effects depending on tumor stage. We have developed novel murine models to determine the effects of modulation of NF-kappaB activity specifically within macrophages during primary mammary tumor growth and metastasis. We have used the cfms promoter to specifically express the reverse tetracycline transactivator (rtTA) protein in macrophages. The rtTA can drive tet operon regulated gene expression in the presence of doxycyline (dox). We have used this with a dominant negative IkappaBalpha to inhibit NF-kappaB signaling in the Polyoma mouse mammary tumor model, this model is termed DNFP. We have also used the cfms-rtTA in combination with a constitutively active IKK2 transgene to activate NF-kappaB signaling, this model is termed IKFM. When NF-kappaB is inhibited in macrophages during primary tumor growth in our DNFP model there is a reduction in primary tumor growth accompanied by a reduced level of lung metastasis. This data suggests that NF-kappaB in macrophages is acting in a pro-tumor manner, in agreement with recently published data. In contrast, we have found that activation of NF-kappaB in macrophages by treating IKFM mice with dox for 1 week before and during two weeks following tail vein injection of polyoma mammary tumor cells leads to a significant reduction in surface lung tumor formation. In additional studies, IKFM mice were pretreated with dox for 1 week but treatment was stopped two days after tumor injection. A similar reduction in tumor number was observed, suggesting an inhibition of cell seeding. Real time PCR analysis of lungs from mice with activation of NF-kappaB in macrophages suggests an anti-tumor “M1” macrophage phenotype. In summary, our data indicates that NF-kappaB activity in macrophages can have both anti- and pro-tumor effects dependent on tumor stage. This data would suggest that cell specificity and timing of treatment are important considerations with regards to the use of NF-kappaB inhibitors in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1352.