Abstract Small airway epithelial cell-derived adenocarcinoma is the most common human lung cancer and is particularly prevalent in women. We have previously reported that the proliferation of immortalized human small airway epithelial cells HPL1D is stimulated by a single dose of the tobacco carcinogen NNK via cAMP signaling activated by binding of NNK to the beta-1-adrenergic receptor (β1-AR) and that estrogen enhances this response. In the current study we show that γ-aminobutyric acid (GABA) blocks this cooperative signaling of NNK and estrogen in HPL1D cells by inhibiting the activation of adenylyl cyclase. In addition, HPL1D cells produced the stress neurotransmitters noradrenaline and adrenaline in response to binding of a single dose of NNK to the α7 nicotinic acetylcholine receptor (α7nAChR). Since both stress neurotransmitters are beta-adrenergic agonists, this response further enhanced cAMP-dependent stimulatory signaling. On the other hand, GABA production by these cells was reduced by a single dose of NNK via desensitization of the α4β2 nAChR. Exposure to NNK, estrogen or the combination of both agents for 7 days upregulated and sensitized the α7nAChR, resulting in an enhanced noradrenergic response to agonist. At the same time, chronic NNK and estrogen suppressed the production of GABA by desensitizing its regulatory α4β2nAChR. The resulting predominance of stimulatory cAMP signaling over inhibitory GABA signaling may contribute to the development and progression of small airway-derived adenocarcinoma in women who smoke and offer a novel target for the marker-guided prevention of this cancer. Supported by a grant from the National Lung Cancer Partnership and LUNGevity Foundation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4124.