Abstract
More patients die from lung cancer than from any other cancer type each year in the United States. Moreover,
lung cancers with K-ras driver mutations are resistant to targeted therapies. Therefore, there is an unmet need
to find druggable targets downstream of K-ras. Tumor-promoting inflammation occurs frequently as a result of
K-ras mutations that activate the NF-¿B pathway, the production of interleukin 6, and activation of its downstream
transcription factor STAT3. However, when we knock out STAT3 in tumor cells in mice, females have fewer
tumors, but males have more. This sex disparity is driven by overactivation of NF-¿B in males, but in females,
estrogen signaling reduces NF-¿B and tumor-promoting inflammation. This protective phenotype requires
estrogen receptors (ERs), nuclear hormone receptors that bind estrogen and interact with NF-¿B. There are two
genes for ERs: ERa and ERß. ERß is the major ER isoform expressed in lung tissue, and ERa is mainly in
immune cells. Accordingly, I hypothesize that in the absence of STAT3 in the lung epithelium, ERa and ERß
signaling is protective in K-ras mutant lung cancer by inhibiting NF-¿B-driven pro-tumor inflammation. I have two
specific aims to test this hypothesis, one aim for each of the cellular compartments of interest: tumor cells and
myeloid cells. Aim 1: I will knock out ERß in tumors to determine if it is required for cancer protection in females.
Aim 2: since ERa predominates in tumor-infiltrating myeloid immune cells, I will knock out ERa in myeloid cells
to determine if it is also required for cancer protection. Successful completion of these aims will further explain
the mechanism of ER-dependent lung cancer protection, with potential for estrogen and ERa/ERß to play a novel
therapeutic role. Since clinical trials for STAT3 inhibitors have begun, it is important to understand the sex-
specific outcomes of targeting STAT3. Our results will guide clinicians to better personalize therapy by taking
sex hormones into account when treating patients. They will also shed light on the mechanism of resistance to
currently available immunotherapies and provide alternative modalities.