Manipulation of Nf-KappaB Activity in the Macrophage Lineage as a Novel Therapeutic Approach

摘要

Morphogenesis of the mammary gland when misregulated can result in tumorigenesis. It involves interactions of multiple cell types in a highly regulated manner with complex signal transduction pathways coordinating the physiological process. Interactions between epithelial and mesenchymal cells are known to be important. Studies have highlighted the importance of macrophages. The nuclear factorkappa B (NF-kB) family of transcription factors appears to be critical in regulating the dynamic changes during normal and neoplastic development. This goal of this proposal was to investigate the contribution of NF-kB signaling within macrophages in normal and neoplastic mammary development. Our data provides insights into the importance of NF-kB signaling in macrophages for mammary and tumor development and progression and suggests the potential for manipulation of NF-kB in macrophages as a novel therapeutic approach. In the course of this study we have used our previously generated IkBa knockout model and more importantly have generated a new set of inducible transgenics that enable us to manipulate NF-kB in macrophages. Our data suggest that altered NF-kappaB activity within macrophages has significant effects on mammary ductal development and impacts at least the metastatic stage of breast tumor progression.