Estrogen receptors restrict tumor-promoting inflammation in K-ras mutant lung cancer

摘要 在美国，每年死于肺癌的患者比死于任何其他癌症类型的患者都多。此外，委员会认为， 具有K-ras驱动突变的肺癌对靶向疗法具有抗性。因此，存在未满足的需求 寻找K-ras基因下游的药物靶点肿瘤促进性炎症经常发生， 激活NF-κB通路的K-ras突变，白细胞介素6的产生及其下游的激活 转录因子STAT 3。然而，当我们敲除小鼠肿瘤细胞中的STAT 3时， 肿瘤，但男性有更多。这种性别差异是由NF-κB在男性中的过度激活引起的，但在女性中， 雌激素信号传导减少NF-κB和肿瘤促进炎症。这种保护性表型需要 雌激素受体（ER），结合雌激素并与NF-κB相互作用的核激素受体。有两 ER基因：ERα和ERβ。ERβ是肺组织中表达的主要ER亚型，ERα主要表达于肺组织中。 免疫细胞。因此，我推测，在肺上皮细胞中缺乏STAT 3的情况下，ERα和ERβ 信号传导通过抑制NF-κ B驱动的促肿瘤炎症在K-ras突变型肺癌中具有保护作用。我有两 为了检验这一假设，每个目标针对每个感兴趣的细胞区室：肿瘤细胞和 骨髓细胞目的1：我将敲除肿瘤中的ERβ，以确定它是否是女性癌症保护所必需的。 目的2：由于ERα在肿瘤浸润的髓系免疫细胞中占主导地位，我将敲除髓系细胞中的ERα 以确定它是否也是癌症保护所必需的。这些目标的成功实现将进一步说明 雌激素依赖性肺癌保护机制，具有潜在的雌激素和ERα/ERβ发挥新的作用 治疗作用。由于STAT 3抑制剂的临床试验已经开始，重要的是要了解性别- 针对STAT 3的具体结果。我们的研究结果将指导临床医生更好地个性化治疗， 在治疗病人时考虑性激素。它们还将阐明耐药机制， 目前可用的免疫疗法，并提供替代模式。

Abstract More patients die from lung cancer than from any other cancer type each year in the United States. Moreover, lung cancers with K-ras driver mutations are resistant to targeted therapies. Therefore, there is an unmet need to find druggable targets downstream of K-ras. Tumor-promoting inflammation occurs frequently as a result of K-ras mutations that activate the NF-κB pathway, the production of interleukin 6, and activation of its downstream transcription factor STAT3. However, when we knock out STAT3 in tumor cells in mice, females have fewer tumors, but males have more. This sex disparity is driven by overactivation of NF-κB in males, but in females, estrogen signaling reduces NF-κB and tumor-promoting inflammation. This protective phenotype requires estrogen receptors (ERs), nuclear hormone receptors that bind estrogen and interact with NF-κB. There are two genes for ERs: ERα and ERβ. ERβ is the major ER isoform expressed in lung tissue, and ERα is mainly in immune cells. Accordingly, I hypothesize that in the absence of STAT3 in the lung epithelium, ERα and ERβ signaling is protective in K-ras mutant lung cancer by inhibiting NF-κB-driven pro-tumor inflammation. I have two specific aims to test this hypothesis, one aim for each of the cellular compartments of interest: tumor cells and myeloid cells. Aim 1: I will knock out ERβ in tumors to determine if it is required for cancer protection in females. Aim 2: since ERα predominates in tumor-infiltrating myeloid immune cells, I will knock out ERα in myeloid cells to determine if it is also required for cancer protection. Successful completion of these aims will further explain the mechanism of ER-dependent lung cancer protection, with potential for estrogen and ERα/ERβ to play a novel therapeutic role. Since clinical trials for STAT3 inhibitors have begun, it is important to understand the sex- specific outcomes of targeting STAT3. Our results will guide clinicians to better personalize therapy by taking sex hormones into account when treating patients. They will also shed light on the mechanism of resistance to currently available immunotherapies and provide alternative modalities.