(PQA2) Elucidating the link between obesity, inflammation and estrogen signaling

描述（由申请人提供）：肥胖已被明确确定为几种类型癌症的重要风险和预后因素，特别是乳腺癌，但肥胖的作用 肥胖与肺癌的关系仍有争议，需要澄清。据报道，体重指数（BMI）和肺癌风险之间存在负相关（1，2）。然而，这些可能是由于吸烟的残留混杂。此外，一些关注饮食因素而不是BMI的流行病学研究表明，高膳食脂肪摄入量与肺癌风险和死亡率之间存在正相关性（3-6）。肥胖增加乳腺癌风险的一个潜在机制涉及通过增加芳香酶活性改变雌激素代谢和通过炎症介质核因子κ-B（NF-：B）介导的雌激素受体信号传导改变（7）。类似的机制是否发生在肺尚未调查，但雌激素信号在肺癌的发展和进展中的作用现在已经确定。肺肿瘤表达雌激素受体和芳香化酶，表达无性别差异（8）。这些标志物在肺肿瘤中的高表达也与肺癌患者的不良预后相关。此外，几项大型队列研究表明雌激素途径与肺癌发生有关，并证明抗雌激素治疗在预防肺癌方面具有保护作用（9，10）。我们最近发现芳香化酶抑制剂阿那曲唑可以抑制烟草诱导的小鼠肺肿瘤发生，并且在该模型系统中，激素信号标记物在浸润小鼠肿瘤前病变和肿瘤的肺部炎性细胞中表达，这表明炎症-芳香化酶联系也存在于肺癌中。此外，雌激素和炎症通路的联合抑制导致小鼠肺部的抗肿瘤作用增强，证实了这两种通路之间的联系。因此，炎症-雌激素信号轴也可能是肥胖和肺癌风险之间联系的基础。 鉴于这些发现，我们假设肥胖通过增加肺部炎症和雌激素释放而增加肺癌风险。该提案的目标是阐明肺癌发生中肥胖、炎症和雌激素信号传导之间的机制联系，从而促进我们对肥胖影响肺癌风险的分子机制的理解。将使用临床前动物模型以及在以下特定目的的实验中的群体研究来解决该假设：1）确定饮食诱导的肥胖在促进由烟草致癌物暴露引起的肺癌发生中的作用以及雌激素途径抑制剂和/或炎性抑制剂降低该作用的能力;和2）确定炎症和/或肥胖的标志物以及循环激素水平与肺癌风险之间的关系。 这项探索性研究是否应该揭示肥胖相关因素与雌激素和/或 由于炎症信号通路在肺肿瘤发生中起作用，在选定的高危人群中涉及激素操纵和/或抗炎治疗的策略可能对肺癌预防有益。

DESCRIPTION (provided by applicant): Obesity has been clearly established as an important risk and prognostic factor for several types of cancer, particularly breast cancer, but the role of obesity in lung cancer remains controversial and requires clarification. Inverse associations between body mass index (BMI) and lung cancer risk have been reported (1, 2). However, these might be due to residual confounding by smoking. Also, several epidemiological studies that focused on dietary factors instead of BMI have shown positive associations between high dietary fat intake and lung cancer risk and mortality (3-6). One potential mechanism by which obesity enhances breast cancer risk involves altered estrogen metabolism through increased aromatase activity and altered estrogen receptor signaling mediated through the inflammatory mediator nuclear factor kappa-B (NF-:B) (7). Whether a similar mechanism occurs in the lung has not yet been investigated, but the role of estrogen signaling in the development and progression of lung cancer is now firmly established. Lung tumors express estrogen receptors and aromatase with no sex difference in expression (8). High expression of these markers in lung tumors has also been correlated with poor prognosis in lung cancer patients. Furthermore, several large cohort studies have implicated the estrogen pathway in lung tumorigenesis and have demonstrated a protective effect of anti-estrogen therapy in the prevention of lung cancer (9,10). We have recently shown that the aromatase inhibitor anastrozole can inhibit tobacco-induced lung tumorigenesis in mice and that hormonal signaling markers are expressed in pulmonary inflammatory cells infiltrating murine preneoplasias and tumors in this model system, suggesting that the inflammation-aromatase link also exists in lung cancer. In addition, combined inhibition of estrogen and inflammatory pathways results in enhanced anti-tumor effects in the lungs of mice, confirming the link between these two pathways. Thus, the inflammation-estrogen signaling axis may underlie the link between obesity and lung cancer risk as well. Given these findings, we hypothesize that obesity contributes to lung cancer risk by increasing both inflammation in the lung and release of estrogen. The goal of this proposal is to elucidate the mechanistic link between obesity, inflammation and estrogen signaling in lung carcinogenesis and thereby advance our understanding of the molecular mechanisms by which obesity affects lung cancer risk. This hypothesis will be addressed using a preclinical animal model as well as a population study in the experiments of the following Specific Aims: 1) Determine the role of diet-induced obesity in promoting lung carcinogenesis caused by tobacco carcinogen exposure and the ability of estrogen pathway inhibitors and/or inflammatory inhibitors to reduce this effect; and 2) Determine the relationship between markers of inflammation and/or obesity as well as circulating hormone levels and lung cancer risk. Should this exploratory study reveal that obesity related factors are linked to the estrogen and/or inflammatory signaling pathways that play a role in lung tumorigenesis, strategies involving hormonal manipulation and/or anti-inflammatory therapies in select high-risk populations may be beneficial for lung cancer prevention.