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Human Non-Small Cell Lung Tumors and Cells Derived from Normal Lung Express Both Estrogen Receptor and ß and Show Biological Responses to Estrogen¹

Department of Pharmacology, University of Pittsburgh [L. P. S., A. L. G. D., C. T. G., T. M. H., J. M. S.], Lung Cancer Program, University of Pittsburgh Cancer Institute [L. P. S., J. D. L., N. C., J. M. S.], Department of Surgery, University of Pittsburgh [J. D. L., N. C.], and Department of Pathology, University of Pittsburgh [S. F.], Pittsburgh, Pennsylvania 15261

Lung cancer is becoming increasingly common in women and in the United States accounts for more female cancer deaths annually than breast cancer. Many epidemiological studies have provided evidence that women are more susceptible than men to the adverse effects of tobacco smoke. These observations suggest the possible role of estrogens in lung carcinogenesis. We report here the expression of mRNA for estrogen receptor (ER) and ß (ERß) in cultured human non-small cell lung cancer cells, cultured lung fibroblasts, and primary cultures of normal bronchial epithelium. Western analysis of ER suggested that the main protein expressed in lung tumor cells is a variant, probably attributable to alternative splicing. Protein for ERß was found to be a mixture of full-length as well as alternatively spliced variants. ß-Estradiol produced a proliferative response in vitro in both normal lung fibroblasts and cultured non-small cell lung tumor cells. This effect was also observed in vivo. In this regard, ß-estradiol stimulated growth of the non-small cell lung tumor line, H23, grown as tumor xenografts in SCID mice. This effect was blocked by fluvestrant (ICI 182,780). In paraffin sections of non-small cell lung tumors, ERß immunoreactivity was localized to the nucleus, whereas ER immunoreactivity was mainly localized to the cytoplasm, suggesting that both nuclear and cytoplasmic signaling may be involved in estrogenic responses in the lung. To show that the ERs found in the lung are functional, we demonstrated that ß-estradiol stimulated transcription of an estrogen response element-luciferase construct transfected in non-small cell lung tumor cell lines. Antiestrogens blocked this effect. Treatment of lung fibroblasts with ß-estradiol also increased secretion of hepatocyte growth factor by 2-fold. These results suggest that estrogen signaling plays a biological role in both the epithelium and the mesenchyme in the lung and that estrogens could potentially promote lung cancer, either through direct actions on preneoplastic or neoplastic cells or through indirect actions on lung fibroblasts. Additionally, it is possible that antiestrogens may have therapeutic value to treat or prevent lung cancer.

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