Abstract Small airway epithelial cell-derived adenocarcinoma is the most common human lung cancer. Previous research from our laboratory has indicated the importance of stress neurotransmitters in cancer signaling in these cells in vitro. In the current study, we have assessed the potential modulation of cancer progression by social stress in xenograph models. The adenocarcinoma cell lines NCI-H322 (with activating point mutations in K-ras) and NCI-H441 (without ras mutations) were injected into nude mice 4 weeks after induction of social stress. The social stress continued for an additional 4 weeks when the tumors were removed. RNA was isolated, and PCR microarrays were used to identify genes that could be affected by stress. Using real-time PCR, we investigated some of these genes. We saw significant decreases in β1-adrenergic (0.49 fold), β2-adrenergic (0.55 fold) and calmodulin (0.16 fold) gene expression in the NCI-H322 xenographs. In the NCI-H441 xenographs, only calmodulin was changed (1.59 fold increase). The immortalized normal human small airway epithelial cell HPL1D was chosen for in-vitro studies. Treatment of HPL1D cells for 7 days with 10 μM acetylcholine led to a significant 0.48 fold decrease in β1-adrenergic gene expression. Previous research from our laboratory has indicated the significance of potassium channels in both lung cancer and breast cancer. Therefore, we determined if a potassium channel could be involved in these stress-induced responses. The voltage-dependent human ether à go-go (EAG) potassium channel has been shown to be important in cellular signaling, cancer progression and calcium signaling/calmodulin binding. After assay by real-time PCR, the NCI-H322 xenographs showed a significant 0.51 fold decrease in EAG gene expression, but there was no change in gene expression in the NCI-H441 xenographs. Treatment of HPL1D cells for 7 days with 10 μM acetylcholine led to a significant 0.36 fold decrease in EAG gene expression. Our data indicate social stress modulates beta-adrenergic and potassium channel-mediated signaling in lung adenocarcinoma. Supported by 1RC1CA144640 with the National Institutes of Health. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1023. doi:10.1158/1538-7445.AM2011-1023