Epidermal growth factor receptor (EGFR) is linked to tumor development and progression through increased cell proliferation, survival, migration, and angiogenesis. Its activity is often abnormally high in many cancers and this correlates with a poor prognosis. The tumor-promoting properties of EGFR are largely due to its ability to activate proliferation and survival signaling pathways, but EGFR also promotes inflammation that might further facilitate tumorigenesis.  Recently, mutations in EGFR have been discovered in lung adenocarcinomas that increase its activity. Transgenic mice that express EGFR with these activating mutations develop adenocarcinomas and bronchioloalveolar carcinomas that have associated inflammation. We hypothesize that these mutations in EGFR not only cause tumor growth through the canonical proliferation and survival signaling pathways, but also by inducing expression of inflammatory mediators that further promote tumorigenesis and metastasis. We propose that cyclooxygenase-2 (COX-2) and CXCL5/ENA-78 are important mediators of this inflammation.  Using isografts and transgenic models, we plan to study whether these inflammatory mediators contribute to tumorigenesis in the context of activating EGFR mutations. Since our preliminary data point to an important role for COX-2, we also plan to test the effects of COX-2 inhibitors. Our experiments will help design rational therapies for tumors with abnormally active EGFR signaling.