Estrogen receptor-alpha isoforms are the main estrogen receptors expressed in non-small cell lung carcinoma

Abstract

&NA; 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&agr; 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&agr; antibodies targeting different epitopes (HC20, 6F11, 1D5, ER&agr;36 and ER&agr;17p). ER&bgr; 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&bgr;‐estradiol, 17&bgr;‐estradiol‐BSA, tamoxifen and their combination in two NSCLC cell lines (A549, H520). ER&agr; transcript and protein detection in NSCLC specimens and cell lines suggests that extranuclear ER&agr; variants, like ER&agr;36, prevail, while wild‐type ER&agr;66 is minimally expressed. In non‐tumor lung, the wild‐type ER&agr;66 is quasi‐absent. The combined evaluation of ER&agr; isoform staining intensity and subcellular localization with sex, can discriminate NSCLC subtypes and normal lung. Overall ER&agr; transcription decreases in NSCLC. ER&agr; expression is sex‐related in non‐tumor tissue, but in NSCLC it is exclusively correlating with tumor histologic subtype. ER&agr; isoform protein expression is higher than ER&bgr;. ER&agr; isoforms are functional and display specific early transcriptional effects following steroid treatment. In conclusion, our data show a wide extranuclear ER&agr;‐variant expression in normal lung and NSCLC that is not reported by routine pathology ER evaluation criteria, limited in the nuclear wild type receptor.