Cytoplasmic estrogen receptor β as a potential marker in human non-small cell lung carcinoma.
OBJECTIVE
Estrogen has been reported to promote an increased susceptibility to lung cancer development. This study focusses on the role of cytoplasmic estrogen receptor β (c-ERβ) in NSCLC.


METHODS
NSCLC (n = 162) cases were analyzed using immunohistochemistry (IHC) for c-ERβ expression and its association with clinicopathological variables. Significance of c-ERβ expression was further examined using in vitro studies in NSCLC cell lines.


RESULTS
Among ERβ and aromatase positive NSCLC females, c-ERβ 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-ERβ and nuclear ERβ (n-ERβ). U0126 (MAPK/extracellular-signal-regulated kinase (ERK) inhibitor) abrogated MAPK phosphorylation, caused by estradiol via c-ERβ, 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.


CONCLUSIONS
The results indicated that ERβ may contribute to NSCLC via non-genomic action of estrogen through its cytoplasmic form, in addition to the genomic actions via n-ERβ. These actions of estrogen in NSCLCs may be abrogated by combination therapy with ICI 182780 and U0126.
Tohoku University Graduate School of Medicine, Department of Pathology, 2-1 Seriyo-machi, Aoba-ku, Sendai, Miyagi-ken 980 8575, Japan.
Mohit Kumar
MK
Verma
Yasuhiro
Y
Miki
Keiko
K
Abe
Hiromichi
H
Niikawa
Hironobu
H
Sasano
D001141:Aromatase / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D002070:Butadienes / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000737:chemistry*; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D047628:Estrogen Receptor alpha / Q000032:analysis; D047629:Estrogen Receptor beta / Q000032:analysis / Q000502:physiology*; D000077267:Fulvestrant; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage
D014408:Biomarkers, Tumor; D002070:Butadienes; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; C113580:U 0126; D000077267:Fulvestrant; D004958:Estradiol; D001141:Aromatase