## 4 Role of Estrogen Receptors in Non-Small Cell Lung Cancer Complication  
To implicate ERs in the complications of NSCLCs, it is essential to determine that the NSCLC tissues are exposed to estrogens either through localized enhanced aromatase expression or via sufficient circulatory estrogens being synthesized and secreted in the gonads. Exposure of the human body to exogenous estrogens is also possible either through administration of synthetic estrogens/phytoestrogens orxenoestrogenic agents. Since both genomic or non-genomic actions of estrogens involve interactions with ERs or other associated receptors (e.g., GPER/EGFR), detecting the expression level of these receptors in the NSCLC tissues may be crucial. Indeed, aromatase activities have been detected in NSCLC cell lines as well as \(\sim\)86% of tumors [108]. A number of studies including one by the [PERSON] group reported the ER prevalence in lung tumors and NSCLC cell lines [113]. Additionally, a relationship of the hormonal status in the cancer-affected tissues with the expression index of ERs has been established. Of note, it is well known that premenopausal women generate large contingents of estrogens as compared to postmenopausal women and men of all age groups. A comparative analysis of ER expression extent in cancer patients, vis-a-vis age/gender group of pre- and postmenopausal women and men, revealed the highest ER expression intensity in the premenopausal women. In this study, the men cancer patients exhibited a minimal ER expression, suggesting a critical role of either circulating or local tissue level of estrogens in the ER expression [120]. Additionally, overexpression of ERs is detected in lung adenocarcinoma. Of the two ER types, the ER\(\beta\) is more abundant in lung cancer. Studies have reported an ER\(\beta\) overexpression in 60-80% of tumors, irrespective of gender [121]. In a noted effort, [PERSON] and associates explained the differential ER\(\alpha\) detection pattern in NSCLC samples using an ER\(\alpha\) antibody (Ab) raised against either a full-length or an N-terminus or a C-terminus ER\(\alpha\) protein. The Ab against the C-terminus ER\(\alpha\) region detected a predominantly cytoplasm-localized protein compared to the one raised against the N-terminus of the protein. The investigators predicted that in NSCLC, ER\(\alpha\) is N-terminal-deleted and lacks the nuclear localization signal [122]. In a similar study on the prevalence of ER\(\alpha\) splice variants, ER\(\alpha\)36 was reported in NSCLC specimens, while wild-type ER\(\alpha\) was minimally expressed. The results of this study claim that in normal lungs, the wild-type ER\(\alpha\) is quasi-absent [123]. In comparison, both in normal physiology as well as in cultured NSCLC cells, the ER\(\beta\) is predominantly localized within the nucleus [49; 122]. A number of studies including that of [PERSON] and colleagues described the ER\(\beta\) nuclear localization as a more reliable prognosis factor contrary to that of the cytoplasmic ER\(\beta\) expression [27]. Studies also claimed that the cytoplasmic and the nuclear ER\(\beta\) co-expression were correlated with a low survival rate compared to the one without co-expression [124]. The ERs are also localized in the plasma membrane [52; 125]. Studies by [PERSON] and teammates claimed the ER involvement in NSCLC progression by modulating the membrane receptor signaling network [126]. It is predicted that the localization of ERs in the specific cellular compartment including plasma membrane, cytoplasm and/or nucleus may have a distinct function and affect the prognosis differentially via a genomic or non-genomic pathway. The ERs expressed by lung bronchial epithelial as well as NSCLC cells respond transcriptionally to E2/17\(\beta\)-estradiol [66; 67; 114]. In a Kras-activated and p53-deletion-induced lung adenocarcinoma mice model, administration of E2/17\(\beta\)-estradiol promoted the tumor progression.