雌二醇和雌激素受体在肺癌中的作用：聚焦性别差异

Background : Lung cancer (LC) is the first and second most diagnosed cancer in males and females, respectively. Despite advancements, LC remains the leading cause of cancer-related mortality worldwide. Recent discoveries have reopened the discussion about the potential influence of hormonal factors on sex differences in LC outcomes. Among these factors, the role of 17beta-estradiol (E2) in LC tumor progression is still unclear. This study aims to understand the influence of E2 and its possible role in cell proliferation and tumor growth in LC. Methods : To study the contribution of E2 to metabolic activity in vitro, we exposed male and female human bronchial epithelial (HBE) cell lines (BEAS-2B, 16HBEC14o-, and HBEC3-KT), and human and murine LC cell lines (NCI-H441, NCI-1650, NCI-1975, A549, LL/2-Luc2) to seven different concentrations of E2 (from 1pM to 1uM), or vehicle (control) in E2-free medium. MTT assay was conducted after 24, 48, and 72hrs of exposure. We then studied specific E2 pathway mechanisms of cell proliferation in selected conditions. To study sex differences in tumor growth in vivo, we orthotopically injected LL/2-Luc2 murine cells into the left lung of 6-9-week-old C57BL/6J male and female mice. The mice were euthanized at 21 days post-injection or before if they reached humane endpoint. Results : HBE cell lines did not show increased metabolic activity in response to physiological E2 concentrations; however, some cell lines showed a significant increase at the highest concentration (1uM) compared with the control. On the other hand, NCI-H441, NCI-1650, and LL/2-Luc2 showed a significant increase at earlier time points and at lower concentrations of E2. A549 and NCI-1975 did not show increased activity at any E2 concentration compared with control. Additionally, we found that LC cell lines with increased metabolic activity showed a significant increase in expression of genes related to angiogenesis (VEGFA), estrogen metabolism (CYP1B1), and ER pathway co-activation (GREB1) compared with their vehicle-treated cells. In contrast, HBE cell lines did not exhibit these changes, even at the highest E2 concentration, although some showed increased metabolic activity. In vivo, our preliminary results have shown an increased survival in female mice compared with male mice at 21 days post-orthotopic injection with LL/2-Luc2. Conclusion : The preliminary data suggests that estrogen signaling stimulates metabolic activity and gene pathways associated with tumor progression in some LC cell lines. These effects may be related to the individual cell lines' ER expression or mutations. Unveiling these and other mechanisms by which E2 increases cell metabolic activity and induces gene expression highlights the translational potential of targeting the ER pathway or its downstream effectors in LC. Our preliminary in vivo mouse model results with LL/2-Luc2 show increased survival in male C57BL6/J mice compared to females.