Cytoplasmic estrogen receptor β as a potential marker in human non-small cell lung carcinoma

Objectives: Estrogen has been reported to promote an increased susceptibility to lung cancer development. This study focusses on the role of cytoplasmic estrogen receptor beta (c-ER beta) in NSCLC. Methods: NSCLC (n = 162) cases were analyzed using immunohistochemistry (IHC) for c-ER beta expression and its association with clinicopathological variables. Significance of c-ER beta expression was further examined using in vitro studies in NSCLC cell lines. Results: Among ER beta and aromatase positive NSCLC females, c-ER beta was significantly associated with greater tumor diameter and tended to be associated with worse overall survival. A549 and LCAM1 cells expressed aromatase, as well as c-ER beta and nuclear ER beta (n-ER beta). U0126 (MAPK/extracellular-signal-regulated kinase (ERK) inhibitor) abrogated MAPK phosphorylation, caused by estradiol via c-ER beta, more effectively than ICI 182780 (ER blocker) in either cell line. However, ICI 182780 completely abrogated the estrogen responsive elements (ERE)-luciferase activity caused by estradiol. Combination therapy with ICI 182780 and U0126 turned out to be far more effective than either treatment alone in either A549 or LCAM1 cells. Conclusion: The results indicated that ER beta may contribute to NSCLC via non-genomic action of estrogen through its cytoplasmic form, in addition to the genomic actions via n-ER beta. These actions of estrogen in NSCLCs may be abrogated by combination therapy with ICI 182780 and U0126.