Estrogen receptors restrict tumor-promoting inflammation in K-ras mutant lung cancer

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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-κB 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-κB in males, but in females, estrogen signaling reduces NF-κB and tumor-promoting inflammation. This protective phenotype requires estrogen receptors (ERs), nuclear hormone receptors that bind estrogen and interact with NF-κB. There are two genes for ERs: ERα and ERβ. ERβ is the major ER isoform expressed in lung tissue, and ERα is mainly in immune cells. Accordingly, I hypothesize that in the absence of STAT3 in the lung epithelium, ERα and ERβ signaling is protective in K-ras mutant lung cancer by inhibiting NF-κB-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 ERβ in tumors to determine if it is required for cancer protection in females. Aim 2: since ERα predominates in tumor-infiltrating myeloid immune cells, I will knock out ERα 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 ERα/ERβ 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.