## 6 G-Protein-Coupled Estrogen Receptors and Non-Small Cell Lung Cancers
In addition, cytoplasmic GPER expression was found as implicated in the manifestation of advanced cancer stages (IIIA-IV), lymph node metastasis and poor differentiation in NSCLCs [158]. Studies by [PERSON] and associates claimed that GPER-driven activation of insulin-like growth factor-I (IGF-I)/IGF-IR via ERK, p38 and Akt stimulation leads to migration of cancer cells [162]. A recent investigation by [PERSON] and colleagues revealed an oncogenic activity of GPER on NSCLC cells via regulation of YAP1/QKI/circNOTCH1/m6A methylated NOTCH1 mRNA signaling [58]. In contrast to these studies, some other investigations claimed that GPER activation inhibited migration of human NSCLC cells via suppressed IKK-\(\beta\)/NF-\(\kappa\)B signaling pathways [57]. Figure 3: Recognized mechanisms of estrogen receptor (ER)-mediated lung cancer progression. Estrogen receptor \(\beta\) (ER\(\beta\)) is the major estrogen receptor expressed in lung cancer, prevailing in cytoplasm, nucleus and mitochondria. The PI3K/IKK/NF\(\kappa\)B, PI3K/AKT/Bcl-XL and RAS/RAF/MAPK/ERK are the activated signaling pathways for regulatory control of cell proliferation, invasion, metastasis, mitochondrial biogenesis and apoptotic suppression. The G-protein estrogen receptor (GPER) is activated by estradiol (E2) binding to intercept the cAMP/PKA/CREB and PI3K/IKK/NF\(\kappa\)B signaling pathways, together modulating a neoplastic transformation. Abbreviations: PKA: Protein kinase A, CREB: cAMP response-element-binding protein, IKK: Inhibitor of nuclear factor-\(\kappa\)B (lkB) kinase, MAPK: Mitogen-activated protein kinase, ERK: Extracellular signal-regulated kinase, AKT: Protein kinase B, SRC: Steroid receptor coactivator, SHC: SHC-transforming protein 1, GRB2: Growth factor receptor-bound protein 2, SOS: DNA repair system. The Agonists and Antagonists of G-Protein-Coupled Estrogen Receptors and Potential Non-Small Cell Lung Cancer Therapy  
GPERs interact with endogenous natural estrogens and their various in vivo metabolites along with different phytoestrogens and xenoestrogens. However, while some of these molecules act as GPER agonists, others act as antagonists. For example, while 17\(\beta\)-estradiol (E2), the major estrogen in female blood, is a predominant ligand of GPER with agonistic activities [163], estrone (E1) and estriol (E3) (the major in vivo 17\(\beta\)-estradiol (E2) natural metabolites) act as antagonists [164]. ICI182780 (fulvestrant), an SERD [165], was likewise reported to be a GPER agonist [166] with a 30-50 nM GPER binding affinity [124]. Similarly, tamoxifen, an SERM, has been reported to act as a GPER agonist in SKBR3 cells [167]. Even the E2 metabolite, the catechol estrogen 2-OH-E2, binds GPER with a high affinity and acts as a GPER antagonist [168]. Additionally, various studies examined the phytoestrogen and xenoestrogen effects on GPERs. Phytoestrogens such as quercetin, genistein, isoflav, flavones, coumestans, lignans, saponins and stilbenes and synthetic estrogenic compounds in pesticides, herbicides and some plastic monomers including polychlorinated biphenyls and dioxins, bisphenols, methoxychlor and alkylphenols activate GPERs [169; 170]. The xenoestrogens, BPA and dichlorodiphenyltrichloroethane (DDT) exhibit a relatively lower affinity toward GPER (at \(\sim\)0.6 mM) contrary to the (2.8-10) mM range for DDT (albeit it also depends on implicit isomer structure) [171]. Figure 4 summarizes the possible estrogen-targeted therapies that could be exploited to arrest the NSCLC tumorigenesis. The mechanisms relate to the inhibition of estrogen action by the competitive inhibitors of estrogen receptors (e.g., tamoxifen), degradation of estrogen receptors (e.g., fulvestrant or ICI182780) or inhibition of estrogen synthesis by aromatase inhibitors (e.g., anastroazole). Other targets of inhibition are GPER (e.g., by G15, G36) or EGFR by EGFR inhibitors (e.g., gefitinib, erlotinib). A number of molecules have been synthesized that exhibit agonistic or antagonistic potentials against GPERs.