Lung cancer is the leading cause of cancer deaths worldwide. While most lung cancers are associated with tobacco use, which is increasing among women, ~10,000 women who never smoked will die of lung cancer this year in the United States alone. Recently, we reported a novel class of somatic activating mutations in the epidermal growth factor receptor (EGFR) in 10-20% on patients with non-small cell lung cancer (NSCLC). Interestingly, these mutations correlate with clinical response to EGFR inhibitory drugs, and are substantially more prevalent in women. Accumulating evidence indicates the importance of estrogen in lung cancer development, and based on preliminary observations, we speculate that estrogen antagonizes the activity of EGFRs in NSCLC. We hypothesize that normal estrogen levels prevent the development of tumors harboring EGFR genetic abnormalities. Consequently, tumors harboring these genetic lesions may arise when estrogen levels decrease (e.g., in post-menopausal women).
The overall goal of this proposal is to better elucidate the cross-talk of EGFR and estrogen in NSCLC derived cells.

• In particular we would like to determine whether an increased estrogen activity could antagonize the oncogenic potential of EGFR and whether inhibition of ER activity will sensitize cells to the action of EGFR selective inhibitors. This will allow us to test the hypothesis that the increased frequency of EGFR mutations in women in post-menopausal women is a result of the decrease in circulating estrogen, which unmasks the oncogenic potential of this class of mutations. Thus, if presumably EGFR mutations arise at similar levels in males and females, we propose that declining estrogen levels in aging women reveals their oncogenic potential, thus explaining why they are detected with increased frequency in NSCLC female patients.
• In addition our research is aimed at elucidating the molecular mechanism of ER and EGFR antagonism in lung cancer.
• In particular we would like to define a role for SOCS-2 as a major player in the cross-talk between ER and EGFR.