## 1 Introduction
Studies in animals support the above predictions with female mice being more sensitive to chemically induced lung carcinogenesis, which tends to be inhibited by ovariectomy [43]. In a study monitoring the implicit activities, [PERSON] and colleagues examined the lung tumor intensity subsequent to estradiol intake (2 \(\upmu\)g per day for 10 weeks). While tumor count and volume declined after ovariectomy contrary to intact female mice, estradiol administration increased the tumor count and volume in the ovariectomized mice compared to untreated female mice. Similar distinctions were observed in male mice administered equal E2 concentration [44]. Estrogens work through estrogen receptors (ERs)--ER\(\alpha\) and ER\(\upbeta\)--either through genomic or nongenomic mechanisms [45; 46]. Using various ER knockout mice models, [PERSON] and colleagues described the importance of ERs in health and physiology [47]. The details of the ER mechanism of action including their genomic and non-genomic activation could be traced in multiple sources [3; 48]. Physiological, ERs are expressed in normal lung tissues as well as in NSCLC and respond transcriptionally to 17-\(\upbeta\)-estradiol or E2 [49; 50]. Besides ER\(\alpha\) and ER\(\upbeta\), other estrogen receptors implicated in the severity of lung cancer are membrane-bound G-protein-coupled estrogen receptors (GPERs). Generally, GPERs are transmembrane proteins. Under physiological conditions, E2-GPER interaction is involved in various rapid non-genomic actions [51; 52]. A high-level GPER expression was observed in human and mice lung cancer tissues and in the lung cancer cell lines. In these cells, the receptors are predominantly located in cytoplasmic cell organelles, such as the Golgi apparatus and endoplasmic reticulum [53; 54]. In addition, under NSCLC aggravated state, cytoplasmic GPER expression was found as being correlated with more advanced cancer stages (IIIA-IV), lymph node metastasis and poor differentiation [53]. A number of progrowth and pro-proliferative pathways are activated by the ligand-bound GPER and thereby activate tumor/cancer progression [55; 56; 57; 58]. Besides ERs (ER\(\upalpha\) and ER\(\upbeta\)) and GPERs, another receptor closely related to estrogen-dependent signaling is the oncogenic protein epidermal growth factor receptor (EGFR). In NSCLC complication, \(\sim\)89% of patients exhibit an EGFR overexpression or mutation. Thus, the EGFR family of tyrosine kinase receptors is one of the most important signaling molecules in NSCLC complication [59]. EGFRs are colocalized with ER\(\upbeta\) in breast cancer and NSCLC cells [60]. In NSCLC, E2 activates the EGFR pathway promoting cell proliferation, survival, angiogenesis, migration and metastases [61]. Additionally, the orphan nuclear receptors, i.e., estrogen-related receptors (ERRs), which have considerable structural and functional similarities with ERs, are implicated in breast cancer complications [62], alongside aggravated tamoxifen resistance in breast cancer cells [63]. Of note, tamoxifen is a selective estrogen receptor modulator (SERMs). ERRs are detected in the lung tissues both in normal [64] as well as NSCLC-affected lung tissues, aggravating the tumorigenesis [65; 66]. A large number of in vitro cell culture and animal model experiments including knockout mice models were conducted to examine the efficacy of anti-estrogen therapies against NSCLC. In these studies, the efficacy of impaired in vivo estrogen synthesis by aromatase inhibitors was examined. Additionally, SERMs such as tamoxifen or selective estrogen receptor downregulators (SERDs) such as fulvestrant were utilized either alone or in combinations of anti-EGFR molecules [67; 68; 69]. [PERSON] and colleagues discussed the importance of using pharmacological GPER modulators [70]. ERRs were also targeted because of their considerable structural and functional similarities with the ERs [65; 66]. Recently, a number of clinical trials have been completed by targeting estrogens and associated molecules against NSCLCs [71; 72; 73].