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: The expression profile of estrogen receptors (ER) in Non-Small Cell Lung Carcinoma (NSCLC) remains contradictory. Here we investigated protein and transcriptome expression of ER[alpha] wild type and variants. Tissue Micro-Arrays of 200 cases of NSCLC (paired tumor/non-tumor) were assayed by immunohistochemistry using a panel of ER[alpha] antibodies targeting different epitopes (HC20, 6F11, 1D5, ER[alpha]36 and ER[alpha]17p). ER[beta] epitopes were also examined for comparison. In parallel we conducted a probe-set mapping (Affymetrix HGU133 plus 2 chip) meta-analysis of 12 NSCLC tumor public transcriptomic studies (1418 cases) and 39 NSCLC cell lines. Finally, we have investigated early transcriptional effects of 17[beta]-estradiol, 17[beta]-estradiol-BSA, tamoxifen and their combination in two NSCLC cell lines (A549, H520). ER[alpha] transcript and protein detection in NSCLC specimens and cell lines suggests that extranuclear ER[alpha] variants, like ER[alpha]36, prevail, while wild-type ER[alpha]66 is minimally expressed. In non-tumor lung, the wild-type ER[alpha]66 is quasi-absent. The combined evaluation of ER[alpha] isoform staining intensity and subcellular localization with sex, can discriminate NSCLC subtypes and normal lung. Overall ER[alpha] transcription decreases in NSCLC. ER[alpha] expression is sex-related in non-tumor tissue, but in NSCLC it is exclusively correlating with tumor histologic subtype. ER[alpha] isoform protein expression is higher than ER[beta]. ER[alpha] isoforms are functional and display specific early transcriptional effects following steroid treatment. In conclusion, our data show a wide extranuclear ER[alpha]-variant expression in normal lung and NSCLC that is not reported by routine pathology ER evaluation criteria, limited in the nuclear wild type receptor.

(C) 2019Elsevier, Inc.