## 10 Estrogen-Related Receptors and Non-Small Cell Lung Cancer  
Estrogen-related receptors (ERRs) are a group of nuclear receptors including ERs. These receptors are implicated in breast cancer complications [62] and tamoxifen resistance in ER-positive breast cancer [63]. For the genetic characterization of ERRs, a repeated genetic analysis was undertaken. Based on the results, ERRs are grouped into the nuclear receptor 3B family (NR3B), comprising ERs, PRs, androgens, mineralocorticoids and glucocorticoids [185]. Three distinct ERRs have been identified to date. The genes responsible for ERR synthesis are ESRRA (_NR3B1_, ERR\(\alpha\)), ESRRB (_NR3B2_, ERR\(\beta\)) and G (_NR3B3_, ERR\(\gamma\)) [186]. Although ERRs exhibit a considerable structural and functional similarity with ERs, they do not have the capacity to bind with natural estrogens and are thus referred to as orphan nuclear receptors [64]. ERR\(\alpha\) has been detected in the adult lung tissues both in normal physiology [64] and in different NSCLC stages. The corresponding expressions were noted as higher in NSCLC stages III and IV compared to those of I and II. The difference was estimated as statistically significant, irrespective of age, gender, pathological grade, T stage and distant metastasis [66]. No study has, to date, reported an ERR\(\beta\) presence in the embryonic or adult human lungs. ERR\(\gamma\) expression has been reported in embryonic lung tissues including those of humans. However, it has not been detected in adult lungs [187]. ERR\(\alpha\) has been implicated both in the proliferation and migration of NSCLC cells. Elevated ERR\(\alpha\) expression has been noticed not only in NSCLC cells but also in xenograft NSCLC mouse models and clinical NSCLC samples. These results indicate a possible diagnostic or post-tarepeutic prognostic role of ERR\(\alpha\) in NSCLC [188; 189; 190]. The effects of ERR\(\alpha\) knockout were examined on lung adenocarcinoma (LUAD) and lung squamous-cell carcinoma (LSCC) cells. The ERR\(\alpha\) knockdown has resulted in LUAD cell synchronization at the G2-M phase transition, but the LSCC cells continued with cell-cycle progression [66]. These observations infer that while LSCC cell proliferation and growth are not affected by ERR\(\alpha\) knockout, the LUAD cells were unable to propagate the cell cycle due to inhibited G2-M transition. These results indicate a cell-line-specific activity of ERR\(\alpha\)[66]. The in vitro cell culture based experiments documented an ERR\(\alpha\) role in cell proliferation and migration. An investigation by [PERSON] and colleagues monitored the effects of ERR\(\alpha\)-specific inverse agonists/small interfering (si) RNA/shRNA on cell-cycle regulation [191]. In a similar observation, [PERSON] and associates reported that in the in vitro cultured A549 NSCLC cells, ERR\(\alpha\) affects the mitochondrial physiology and quenches ROS generation which suppressed the tumor suppressor protein p53 and pRB expressions. This caused an unhindered cell-cycle progression. The ERR\(\alpha\) modulates multiple cell signaling pathways related to cell-cycle progression, together resulting in accelerated cell division and aggressive tumor progression [189]. A number of studies highlighted the ERR\(\alpha\) involvement in aggressive epithelial-mesenchymal transition (EMT), together contributing to enhanced NSCLC cell migration. In one such attempt, [PERSON] and colleagues [192] treated A549 NSCLC cells with ERR\(\alpha\) inverse agonist XCT-790 and observed the ERR\(\alpha\) involvement in epithelial-mesenchymal transition (EMT). Another significant investigation by [PERSON] and colleagues observed ERR\(\alpha\)-induced pro-inflammatory cytokine IL-6 expression via NF-\(\kappa\)B activation and cytoplasm to nucleus translocation [193]. Notably, it was previously demonstrated that di (2-ethylhexyl) phthalate (DEHP)-induced NSCLC migration and invasion needed an IL-6 upregulation [194; 195].