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  • Estrogen receptors ERs belong to the third class of


    Estrogen receptors (ERs) belong to the third class of nuclear receptors (NR3) [23]. Two different forms of ER have been described, ERα and ERβ. They are coded by two distinct genes (ESR1 and ESR2, respectively) containing 8 transcribed exons that give rise to six conserved protein domains: domains A/B, localized at the N′-terminal part and containing the transcription activation function 1 (AF1), a ligand-independent transcriptional activator and site of ligand-independent co-modulators binding; the highly conserved domain C (DNA-binding domain); domain D, also called the hinge region (epicenter of recruitment, binding and function of clemastine receptor co-modulators and post-translational modifications); finally, domains E and F contain the ligand binding domain (LBD), together with the transcriptional activation function 2 (AF2), a ligand-dependent modulator of transcription [23]. Splice variants have been described for both ERα and ERβ. In addition to their classical actions as nuclear transcription factors, the combined discovery of receptor variants and alternative, extra-nuclear, steroid-initiated signaling pathways, provided new insights in estrogen actions and regulation [23]. To date, ERα36 [24] and ERα46 [25] represent the major estrogen-responsive isoforms of ERα. ERα36 derives from an alternative transcription initiation site at the first intron, containing exons 2–6 of wild-type ERα and a unique C′-terminal 27-amino clemastine sequence (exon 9) [24] (lacking AF1 and part of AF2). ERα46 is another exon 1 -deprived ERα variant [25], containing all other exons of the wild-type receptor. Several variants of ERβ have also been described (ERβ2, ERβ4, ERβ5) [23], lacking various C′-terminal sequences. Traditionally, ERβ is considered the preponderant ER form in the lung [3]. ERβ’s relation to patients’ survival remains controversial [26], [27]. ERα mRNA and protein have also been detected in lung tumor specimens and cell lines [18], [26], [28]. Biologically-active ERα spliced variants have been detected in a number of carcinomas [29], [30], [31] including NSCLC [18]. This was suggested by in vitro and in vivo data on responsiveness of lung ERα to estrogen, as well as to ERα antagonists or aromatase inhibitors [12], [13], [14], [16], [18], [32], [33], [34], [35], [36], [37]. ERα detection and evaluation of its biologic relevance present a certain degree of complexity, mainly related to receptor heterogeneity and diversity of functions [23]. ERα is a dynamic protein, translocating within intracellular compartments. In addition to genomic transcriptional actions, the receptor triggers specific cytoplasmic/membrane signaling events and establishes cross-talk with other receptors (e.g. growth factor) [38]. Furthermore, ERα is submitted to several post-translational modifications, while proteasomal degradation may generate peptides with modulatory potential on transcription, cell fate and migration [39], [40], [41], [42]. Hence, optimal choice of the appropriate antibodies and antibody validation for ERα detection are crucial [43].
    Material and methods
    Discussion The role of estrogen in lung physiology and disease is poorly understood and controversial. Clinical evidence suggests that female sex is associated with poorer prognosis in asthma, chronic obstructive pulmonary disease or cystic fibrosis [4], [5], [6], [7], [8], [9]; in contrast, female lung cancer patients respond better to treatment and have a lengthened survival. Although ER pulmonary expression gains increasing interest, it remains a matter of controversy: ERβ is considered the predominant estrogen receptor in the lung [3], while the expression and biologic relevance of ERα remain a matter of debate. This is partially attributed to: (1) the high heterogeneity of the receptor and the abundance of its splice variants/isoforms, (2) differences in ER antibodies sensitivity/specificity [62], (3) the difficulties of identification of functional receptors, and finally, (4) the nuclear and/or extra-nuclear receptor localization [23]. In routine pathology diagnostics, only the nuclear ERs are taken into account. However, an expanding volume of publications report specific extranuclear ER actions, different from those initiated by nuclear ERs [23]. Therefore, a “paradigm shift” on the pathologist detection, scoring and reporting of extranuclear ER localization the integration of those extranuclear actions in possible therapeutic decisions would be highly anticipated. Such an approach is presented in this work. Aim of the present study was to assess the expression of ERα (ESR1 gene coded) estrogen-responding (iso)forms (wild-type ERα and ERα46 and ERα36 variants) in NSCLC and non-tumor lung tissue.