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Steroids. 2019 Feb;142:65-76. doi: 10.1016/j.steroids.2018.01.008. Epub 2018 Feb 15.

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

Author information

1
Laboratory of Pathology, School of Medicine, University of Crete, Heraklion, Greece; Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklion Greece; Department of Pathology, Yale School of Medicine, New Haven, CT, United States. Electronic address: vasiliki.pelekanou@yale.edu.
2
Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklion Greece.
3
Yale Medical Library, Yale School of Medicine, New Haven, CT, United States.
4
Laboratory of Pathology, School of Medicine, University of Crete, Heraklion, Greece.
5
Metaxa Cancer Hospital, Piraeus, Greece.
6
Molecular Histopathology Laboratory, Dept. of Pathology, Royal College of Surgeons of Ireland (RCSI), Education & Research Centre, Dublin, Ireland; Beaumont Hospital, Dublin, Ireland.
7
Department of Medical Oncology, University General Hospital, Heraklion, Greece.
8
Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklion Greece; INSERM U976, Hôpital Saint Louis, Paris, France; Université Paris Diderot, Paris, France.

Abstract

The expression profile of estrogen receptors (ER) in Non-Small Cell Lung Carcinoma (NSCLC) remains contradictory. Here we investigated protein and transcriptome expression of ERα wild type and variants. Tissue Micro-Arrays of 200 cases of NSCLC (paired tumor/non-tumor) were assayed by immunohistochemistry using a panel of ERα antibodies targeting different epitopes (HC20, 6F11, 1D5, ERα36 and ERα17p). ERβ 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 17β-estradiol, 17β-estradiol-BSA, tamoxifen and their combination in two NSCLC cell lines (A549, H520). ERα transcript and protein detection in NSCLC specimens and cell lines suggests that extranuclear ERα variants, like ERα36, prevail, while wild-type ERα66 is minimally expressed. In non-tumor lung, the wild-type ERα66 is quasi-absent. The combined evaluation of ERα isoform staining intensity and subcellular localization with sex, can discriminate NSCLC subtypes and normal lung. Overall ERα transcription decreases in NSCLC. ERα expression is sex-related in non-tumor tissue, but in NSCLC it is exclusively correlating with tumor histologic subtype. ERα isoform protein expression is higher than ERβ. ERα isoforms are functional and display specific early transcriptional effects following steroid treatment. In conclusion, our data show a wide extranuclear ERα-variant expression in normal lung and NSCLC that is not reported by routine pathology ER evaluation criteria, limited in the nuclear wild type receptor.

KEYWORDS:

Estrogen receptor-alpha; Immunostaining; Lung; Meta-analysis; Microarrays; NSCLC

PMID:
29454903
DOI:
10.1016/j.steroids.2018.01.008
[Indexed for MEDLINE]

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