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The higher frequency of lung cancer in women than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer. Women smokers are more likely to develop lung adenocarcinoma. Historically, lung was not considered an estrogen target tissue, but recent studies have shown that assumption to be false. Biological responses to estrogens are mediated by two estrogen receptors (ER), ERα and ERβ. The expression of ERα expression in lung and lung tumors is unclear. ERβ is expressed in normal human lung and in lung adenocarcinomas. The biological role of ER in lung is unknown, but in other tissues, ERβ is antiproliferative whereas ERα is proliferative. The hypotheses tested in this project were 1) human lung adenocarcinoma cell lines express ERα > ERβ. 2) ER is functionally active in lung cancer cell lines. 3) Estrogen antagonists block replication of lung cancer cells. 4) Resveratrol, a phytoestrogen with chemopreventive activity, blocks lung cancer cell replication. ERα and ERβ expression was evaluated by real time RT-PCR and Western blot. Lung cancer cell proliferation was measured after treatment with estradiol (E2); resveratrol; the estrogen antagonists 4-hydroxytamoxifen (4-OHT) and ICI 182,780; and carcinogenic constituents of cigarette smoke: benz[a]pyrene, cadmium, and arsenite. Transient transfection of lung cancer cells with an estrogen response element reporter was used to evaluate E2 and other ligand-driven transcription. Results showed that ERα and ERβ proteins were expressed in all cell lines. Resveratrol blocked proliferation of lung cancer cells in a concentration-dependent manner with higher efficacy in lung than breast cancer cells. Importantly, all adenocarcinoma cell lines from female lung cancer patients proliferated in response to E2 and cell replication was inhibited by 4-OHT. In contrast, E2 had no effect on the replication of adenocarcinoma cells from male lung cancer patients and 4-OHT did not block their growth. Thus, ERα and ERβ expression does not correlate with the effect of ER ligands on cell proliferation. The uncoupling of ERα and ERβ expression from biological response indicates that downstream components of ER signaling, e.g., coactivators or corepressors, may be missing in male lung adenocarcinoma cell lines. The clinical ramification of these results suggests that tamoxifen may be a useful therapeutic intervention to block adenocarcinoma cell proliferation in women, but not men, with lung cancer.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]