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Nongenomic ß Estrogen Receptors Enhance ß1 Adrenergic Signaling Induced by the Nicotine-Derived Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Human Small Airway Epithelial Cells

¹ Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee and ² Division of Molecular Carcinogenesis, Center of Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

Requests for reprints: Hildegard M. Schuller, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996. Phone: 865-974-8217; Fax: 865-974-5616; E-mail: hmsch{at}utk.edu.

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 ß (ERß) is the predominating form. We found that 17ß-estradiol enhanced proliferation of the putative cells of origin of lung adenocarcinoma, small airway epithelial cells (HPLD1), in response to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Reverse-phase protein microarrays combined with Western blotting revealed that NNK induced phosphorylation of ERß, an effect that involved stimulation of the adrenergic receptors ß1 (ß1AR). In transiently transfected cells, ß1AR coprecipitated with ERß, which increased with NNK treatment. ERß enhanced NNK-induced cyclic AMP accumulation as well as Gi-mediated mitogen-activated protein kinase/extracellular signal–regulated kinase (ERK) 1/2 activation. Coexpression of ß1AR and ERß activated NNK-mediated ERK1/2 cooperatively. ERß 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 Thr³⁰⁸ and Ser⁴⁷³, ERß had no effect on this activity. Luciferase reporter assays showed that, in response to NNK, ERß 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 ERß, the dependence on Gi proteins, the activation of ERK1/2, and the preferential targeting of SRE over the classic ERE pathway support a role for nongenomic ERß in the development of smoking-associated lung cancer. This novel cooperation between ß1AR and ERß signaling may contribute to the prominence of lung adenocarcinoma in women. [Cancer Res 2007;67(14):6863–71]

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