## 6 G-Protein-Coupled Estrogen Receptors and Non-Small Cell Lung Cancers
The most important of these are G-1, G-15 and G-36. Figure 5 depicts the chemical structures of G-1, G-15 and G-36 GPER antagonists, distinguished in terms of alkoxy, null and extended alkyl chain substitutions at the ortho positions of the terminal phenyl ring. A common prospect for designing more potent analogs inferred from these structures is the presence of nitrogen and hydrogen together (intramolecular hydrogen bonding), bromine as a substituent, in and out of the plane symmetries of hydrogen atoms, distributed pi-conjugation (hydrophobic receptivity) and five-membered ring having two oxygens (controlling oxidative balance). In 2006, [PERSON] and colleagues identified the GPER-selective agonist G-1 [172; 173]. The antagonist G-15 was discovered in 2015 and exhibits a 0.5-fold stronger binding compared to G-1 along with a 1000-fold selectivity toward ER\(\alpha\) and ER\(\beta\)[174]. Another GPER antagonist, G-36, was synthesized by [PERSON] and associates in 2011. Compared to G15, G-36 has been in wide use for GPER study owing to its lower off-target activity and weaker cross-reactivity with ER\(\alpha\)[175]. The binding affinity of various agonists and antagonists varies, and therefore specific concentration being used in experiments is highly diligent. Recently, [PERSON] and colleagues showed that GPER antagonist G15 decreases estrogen-induced development of NSCLC [53]. This study concluded that GPER may have the potential to be used as a therapeutic target against NSCLC manifestation. Toward this direction, two separate comprehensive review articles by [PERSON] and [PERSON] groups described the potential of various GPER agonists or antagonists as therapeutic agents against various diseases [176; 177]. More clinical studies are necessary to evaluate the anti-NSCLC GPER regulation. Figure 4: Possible NSCLC treatment mechanisms for estrogen signaling pathway targeted NSCLC treatment, comprising (1) aromatase suppression using the inhibitor anstrazole, (2) impaired activity of ERs using pure anti-estrogen fulvestrant, (3) impaired GPR30-driven signaling via antagonist G15 and (4) targeting the estrogen-activated growth factor pathways, mainly EGF and VEGF, using gefitinib, erlotinib and vandetanib drugs. These strategies can be used in singular as well as in combination mode. Figure 5: Chemical structures of the GPER antagonists, G-1, G-15 and G-36. The structures of these compounds distinguish an influence of extended alkyl, alkoxy and null substitution in the terminal rings. Though G-36 has been reported only recently for its reduced non-specific response, the G-15 has been listed in 2019 only for its anti-estrogen-mediated control of NSCLC growth. Interactions of Estrogen Receptors and Epidermal Growth Factor Receptors for Aggravated Tumorigenesis in Non-Small Cell Lung Cancers  
The oncoprotein epidermal growth factor receptors (EGFRs) are a family of tyrosine kinase receptors. In NSCLC manifestation, EGFR-mediated signaling remains one of the most important pathways since 89% of NSCLC patients exhibit either EGFR overexpression or mutation [59]. The EGFR is known to be involved in NSCLC growth, protection against apoptotic defense and regulation of angiogenesis [67]. In NSCLC, E2 activates the EGFR pathway promoting cell proliferation, survival, angiogenesis, cell migration and metastasis (Figure 6) [61]. A number of studies claimed that considerable EGFR and ER cross-talk prevails in NSCLC pathogenesis. In 87.5% of the ER-positive lung tumors, serine residues in the ER molecules phosphorylate the EGFR although ligand involvement in this cross-talk was not confirmed [26; 127]. However, other studies claimed that estrogens bind with membrane-bound ERs to activate the cytoplasmic signaling pathways including that of EGFR signaling pathways [178]. Membrane ERs were also found to be co-localized with EGFR in lung tumors [60]. Figure 6: Schematic description of EGFR–ER interactions, initiated by ER dimmers on binding the carboxyl terminal region of EGFR in the cytosol.