Women are at higher risk for the development of lung adenocarcinoma than men; however, the mechanisms responsible for this are poorly understood. In lung adenocarcinoma cells, the estrogen receptor B (ERB) is the predominating form. We found that 17B-estradiol enhanced proliferation of the putative cells of origin of lung adenocarcinoma, small airway epithelial cells (HPLD1), in response to the nicotinederived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Reverse-phase protein microarrays combined with Western blotting revealed that NNK induced phosphorylation of ERB, an effect that involved stimulation of the adrenergic receptors B1 (B1AR). In transiently transfected cells, B1AR coprecipitated with ERB, which increased with NNK treatment. ERB enhanced NNK-induced cyclic AMP accumulation as well as GAi-mediated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 activation. Coexpression of B1AR and ERB activated NNKmediated ERK1/2 cooperatively. ERb gene knockdown, as well as coexpression of the dominant negative Ras and Raf, reduced stimulation of ERK1/2 by NNK. Whereas NNK phosphorylated Akt at Thr 308 and Ser 473 , ERB had no effect on this activity. Luciferase reporter assays showed that, in response to NNK, ERB stimulated transcription of serum responsive element (SRE) but had a very small effect on the activity of estrogen responsive element (ERE). Together, the phosphorylation of ERB, the dependence on GAi proteins, the activation of ERK1/2, and the preferential targeting of SRE over the classic ERE pathway support a role for nongenomic ERB in the development of smoking-associated lung cancer. This novel cooperation between B1AR and ERB signaling may contribute to the prominence of lung adenocarcinoma in women.