Increasing evidence shows that women are more vulnerable to lung cancer than men, suggesting that estrogen plays a role in the pathology of this cancer. Cigarette smoke contains enormous estrogen-like polycyclic aromatic hydrocarbons that may alter the activity of estrogen receptors (ERs) directly or indirectly through aryl hydrocarbon receptor (AhR). Here we examine estrogenic and antiestrogenic effects of a condensate of cigarette side-stream particulates (CSSP) in lung cancer cell lines that are engineered to exhibit different ER/AhR phenotypes by reporter transfection analysis. Our results show that the CSSP condensate (0–20 μg/ml) has similar dose-dependent estrogenic effects on ERa and ERb in the absence of estradiol (E2). Co-expression of AhR does not affect the estrogenic effects of CSSP. The estrogenicity of CSSP at 20 μg/ml is comparable to that exhibited by 1 nM E2 in all the cell lines examined. Cotreatment of cells with CSSP and E2 leads to an additive estrogenic response in ERa+ cells, whereas the cotreatement does not alter or improve E2-induced ERb activation. To check whether the estrogenic activity of CSSP is mediated through ERa and ERb, a pure antiestrogen compound ICI 182780 is used to block the binding of ligands to these ERs. ICI 182780 at 10 nM can efficiently prevent E2 from activating ERa and ERb. This concentration of ICI 182780 does not affect the estrogenic effect of CSSP on ERa regardless of the presence and absence of E2, but it reduces the estrogenic effect on ERb. These results suggest that (1) CSSP can activate ERa and ERb by a mechanism independent of ligand binding, and (2) CSSP contains some components that can act as ERb ligands.
