Non-small cell lung cancer is the most common cause of cancer related deaths in the US and novel agents targeting this disease have shown considerable promise.  Some recent clinical trials evaluating receptor tyrosine kinase inhibitors such as bevacizumab and ZD6474 have shown gender specific differences in therapeutic efficacy.  These differences suggest that factors inherent in the male/female biology may have a significant impact in RTK activities and their subsequent inhibition.  Recent data suggests that estrogen and EGF can synergistically activate the EGFR downstream effectors, including ERK1/2, and may that each impact critical angiogenic pathways including HIF 1-alpha.  We propose that the EGFR and ER pathways may cooperatively interact to increase angiogenesis and enhance EGFR dependence.  We will evaluate this hypothesis by in vitro examining the role of estrogen and hypoxia in EGFR mediated signaling and the angiogenic factor production in bronchioalveolar, adenocarcinoma, and squamous carcinoma cell lines.  Using the novel reverse phase lysate arrays (RPPA) and multiplex bead analysis, we will analyze differentially activated signal transduction pathways and secreted angiogenic factors.  In Aim 2 we will utilize a transgenic mouse model of bronchioalveolar carcinoma to analyze the effects of estrogen signaling in EGFR dependent tumor initiation and maintenance.  Finally, by modulating estrogen signaling in an in vivo xenograft model of NSCLC we will examine the role of estrogen signaling in the therapeutic efficacy of RTK inhibitors.  These studies aim to reveal the molecular mechanisms underlying gender specific differences in the development of BAC and the responsiveness to angiogenesis inhibitors. This knowledge may help guide therapeutic strategies to enhance the efficacy of antinagiogenic therapy.