## 4 Role of Estrogen Receptors in Non-Small Cell Lung Cancer Complication
In this experimental mice model, male and ovariectomized female mice respond likewise in response to17\(\beta\)-estradiol administration [44]. The poorer clinical outcomes observed in NSCLC patients may be related to the proliferative as well as survival responses to 17\(\beta\)-estradiol. A number of studies documented the specific cell signaling moleculesand associated pathways involved in the 17\(\beta\)-estradiol dependent proliferation, survival and growth of in vitro cultured NSCLC cell lines and tumor xenografts [60; 67; 121; 127]. However, there is a lot of controversy regarding beneficial versus adverse effects of HRT in the human body [14; 15]. Similarly, the role of ERs in NSCLC remains controversial, and the mechanisms of action of ERs in NSCLC complications are not conclusive. There is no consensus on whether ER\(\beta\) expression plays a role in survival. Some studies have suggested a protective effect of ER\(\beta\) nuclear expression [128; 129; 130], which may only be significant in men [130]. It is possible that the presence of nuclear ER\(\beta\) confers a hormonal dependence for growth rather than on the other more aggressive oncogenic pathways, leading to a comparatively better survival. A number of comprehensive review articles described various aspects of ERs in the NSCLC complication [55; 131]. 5 Efficacy of Anti-Estrogen and Anti-Estrogen Receptor Molecules against Non-Small Cell Lung Cancers  
Aromatase inhibitors that include irreversible steroid inhibitors/non-steroidal inhibitors (e.g., anastrozole, letrozole, etc.) and selective ER modulators (SERMs, e.g., tamoxifen, a competitive inhibitor with equal ER\(\alpha\) and ER\(\beta\) affinity) or selective ER downregulators (SERDs, e.g., fulvestrant/ICI182780, a pure anti-ER molecule with equal affinity for ER\(\alpha\) and ER\(\beta\) which degrades both ER\(\alpha\) and ER\(\beta\)) are used against estrogen/ER-dependent cancers. The efficacy of these molecules against NSCLC complication was examined by in vitro cell culture and animal model experiments including xenograft and ER knockout mice models and clinical studies involving NSCLC patients. Details of the estrogen activities in lung cancer complication, particularly in women, have been recently reviewed [132; 133]. In cell culture experiments using A549 NSCLC cells, it was shown that lowering the estrogen concentration inhibited the A549 cell's growth [134]. Another significant in vitro study revealed that aromatase inhibitors such as letrozole significantly decreased cell proliferation while exemestane reduced tumor growth and increased cell apoptosis, alongside inhibiting cell migration and invasion [135]. The efficacy of the SERD molecules such as fulvestrant was also examined in the in vitro cell culture based experiments and tumor xenograft mouse model. The results of these studies show significant inhibition of 17\(\beta\)-estradiol-induced NSCLC (cell lines) grown in culture and as tumor xenografts. In this study, the combined activity of anti-ER and anti-EGFR molecules emerged more efficacious pertaining to the anti-NSCLC activities [67]. A number of similar experimental studies focused on the efficiency of fulvestrant in NSCLC suppression [106; 137; 136]. Data presented by [PERSON] and colleagues showed that dexamethasone suppresses the growth of NSCLC cell line A549 injected xenograft tumors via inducing estrogen sulfotransferases and decreasing estradiol levels in tumor tissues, suggesting that dexamethasone may be used as an anti-estrogenic agent for the NSCLC treatment [138]. Clinical observational studies consisting of 6500 breast cancer survivors subjected to anti-estrogen therapy showed lower subsequent lung cancer mortality [139]. In another similar study consisting of 2320 patients, a strong anti-estrogen therapy and lung cancer motility correlation was observed [140]. More recently, three separate and independent clinical trials have been conducted to evaluate the anti-estrogen/anti-ER therapeutic efficacy toward lung cancer [71; 72; 73].