NF-kappaB signaling can regulate a diverse set of processes including proliferation, apoptosis, angiogenesis and inflammation. During the progression from normal mammary development to hyperplasia, primary tumor formation and finally to metastasis a complex interplay of these processes occurs. The proposed project will define the role of NF-kappaB signaling as a master regulator of these processes, integrating multiple processes and thereby determining ultimate physiological outcome. As such, modulation of NF-kappaB signaling represents an important strategy for therapeutic intervention and considerable research effort is being expended to identify inhibitors of NF-kappaB functional at various stages of the signaling cascade. Signaling pathways that are active are likely to be different during particular stages of tumorigenesis eg. normal development, primary tumor growth and metastasis. It is therefore important to understand the complexities of the regulatory pathways to determine the most efficacious points to target therapy and to minimize undesirable side effects. We propose utilizing several existing murine models to examine the effect of modulation of NF-kappaB activity within mammary epithelium on the continuum of mammary tumorigenesis. Our strategy will address both activation and inhibition of the classical p50/p65/lkappaBalpha pathway and stimulation of the alternative RelB/p1007p52 pathway. We will clarify the effects of modulating NF-kappaB activity during development, primary tumor formation and metastasis on critical processes such as proliferation, apoptosis, angiogenesis and inflammation. It is hypothesized that modulation of NF-kappaB activity will have significant effects at all stages of tumor development and progression on pathogenic outcome. These studies will provide powerful data that will increase our knowledge of the roles of NF-kappaB in mammary tumorigenesis, thus supporting the design of informed therapeutic strategies.
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