## 1 Introduction
This comprehensive review article sheds light on the role of endogenous and exogenous estrogens as well as ERs, GPERs, EGFRs and ERRs in the NSCLC complication and the efficacy of targeting these molecules in the NSCLC subjects. Exposure of Mammalian Lungs to Endogenous and Exogenous Estrogens Including Synthetic Estrogens, Phytoestrogens and Xenoestrogens  
Under thoroughly normal physiological conditions, females express high levels of aromatase (CYP19A1) enzymes from the granulosa cells of Graafian follicles within the ovaries. In the process of steroidogenesis, aromatases catalyze testosterone-to-estrogen conversion. Thus, in complete normal physiological conditions, a female body by itself (naturally) contains a large amount of estrogens with a proportionately low level of testosterone. These naturally produced estrogens have physiological roles both in gonadal and nong gonadal tissues. In comparison, the Leydic cells of testes (in males) synthesize a low level of estrogens owing to a weaker aromatase activity, resulting in concurrent testosterone accumulation along with its subsequent conversion to dihydrotestosterone (dHT) through the action of 5-\(\alpha\)-reductase [6; 7; 32]. Estrogens once produced from the gonadal tissues (ovary/tests) are released into the circulation, ultimately reaching various body parts including lungs. Besides major synthesis in the gonads, a low level of aromatases is also locally expressed in nongonadal tissues which are capable of synthesizing estrogens that complicate the cancerous progressions [74]. The 17-\(\beta\) estradiol (E2) is the major estrogen present in the female circulation with a half-life of 3.5 h [10], which is metabolized to estrone (E1) and estrol (E3) within the liver. Collectively, E1, E2 and E3 are the major backbone of various estrogens expressed in the mammalian body. Some other estrogen-active metabolites produced in the mammalian body include catechol estrogens (2-OH-E-2 and 4-OH-E-2), which are further metabolized into highly reactive estrogen quinones (E2-2,3-Q and E2-3,4-Q) [11; 75; 76]. Some of the estrogen metabolites such as 4-OH-E2, a product of the CYP1B1 enzyme, exhibit mutagenic and carcinogenic effects [77]. The 17-\(\beta\)-estradiol-to-4-OH-E2 metabolic conversion is induced via cigarette smoke exposure. In various tissues including lungs, estrogen metabolites regulate the mutation and subsequent proto-oncogenes-to-oncogenes conversion which increases the lung cancer risk [78]. The development of lung cancer in humans may be associated with gene deletions on the chromosomes 1, 3, 11, 13 and 17. Prominent proto-oncogenes induced by these genetic aberrations include c-jun, ras and c-raf1 along with a loss of tumor suppressor gene p53. Amongst these, c-erbB-2, c-sis and c-fes are prominently expressed or missing in the NSCLC and can be of substantial importance in the selection of a differentiation pathway. Preclinical studies have revealed major NSCLC proliferative activities regulated through genomic and indirect non-genomic mechanisms of E2. The c-myc oncogene is often noted as being amplified in small-cell lung cancer (SCLC) cell lines. Investigations demonstrate the ER influence on NSCLC cells mediated via EGFR-signaling-driven cell-cycle regulation, the cAMP, MAPK and AKT pathways and the promotion of c-myc and cyclin D expressions [79; 80]. Despite being well-known for estrogen induction, the c-myc promoter does not possess any estrogen-response elements (EREs). While exact investigations tracing estrogen response in NSCLC are rather too scarce, the results from the modulated expressions in other tumors (primarily breast) indeed offer a basis of functional link. A 2011 study of this kind discussed the experience of distant elements being involved in estrogen-induced gene expression. Analysis revealed an insignificant effect on c-myc proximal promoter activity, though it stimulated the activity of a luciferase reporter characterized by a distal 67 kb enhancer.