Targeting Estrogens and Various Estrogen-Related Receptors against Non-Small Cell Lung Cancers: A Perspective

SIMPLE SUMMARY: Exogenous and endogenous estrogens and associated receptors modulate signaling pathways with biochemical events implicated in non-small cell lung cancer (NSCLC) manifestation. The diversity of biochemical interactions initiated by estrogens is rigorous, regulated via distinct estrogen-associated receptors. While estrogen receptor beta (ERβ) is overexpressed in 60–80% of NSCLCs irrespective of gender, the recognition of transmembrane G-protein-coupled estrogen receptor (GPER) creates several interfaces of estrogen-interception-driven aggressive NSCLC manifestation. There is still room for understanding the crux of ER–EGFR (epidermal growth factor receptor) interactions considering the recent clinical trials revealing a synergistic anti-NSCLC response. With such insights, this manuscript presents a comprehensive discussion on the sequential biochemical events in estrogen-activated cell signaling pathways in NSCLC complications with a focus on the ER/GPER/EGFR/ERR regulatory mechanism alongside the NSCLC treating anti-estrogen targeted therapies. ABSTRACT: Non-small cell lung cancers (NSCLCs) account for ~85% of lung cancer cases worldwide. Mammalian lungs are exposed to both endogenous and exogenous estrogens. The expression of estrogen receptors (ERs) in lung cancer cells has evoked the necessity to evaluate the role of estrogens in the disease progression. Estrogens, specifically 17β-estradiol, promote maturation of several tissue types including lungs. Recent epidemiologic data indicate that women have a higher risk of lung adenocarcinoma, a type of NSCLC, when compared to men, independent of smoking status. Besides ERs, pulmonary tissues both in healthy physiology and in NSCLCs also express G-protein-coupled ERs (GPERs), epidermal growth factor receptor (EGFRs), estrogen-related receptors (ERRs) and orphan nuclear receptors. Premenopausal females between the ages of 15 and 50 years synthesize a large contingent of estrogens and are at a greater risk of developing NSCLCs. Estrogen—ER/GPER/EGFR/ERR—mediated activation of various cell signaling molecules regulates NSCLC cell proliferation, survival and apoptosis. This article sheds light on the most recent achievements in the elucidation of sequential biochemical events in estrogen-activated cell signaling pathways involved in NSCLC severity with insight into the mechanism of regulation by ERs/GPERs/EGFRs/ERRs. It further discusses the success of anti-estrogen therapies against NSCLCs.