Lung Cancer in Never-smokers: Role of Estrogen and its Metabolites

从不吸烟者的肺癌：雌激素及其代谢物的作用

基本信息

批准号：
10338105
负责人：
MARGIE L. CLAPPER
金额：
$ 41.92万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338105
关键词：
Anchorage-Independent Growth Appearance Attention Autopsy BRAF gene CYP1B1 gene Cancer Etiology Cancer Patient Carcinogens Catechol O-Methyltransferase Cessation of life Characteristics Clinical Complement Conflict (Psychology)Cytochrome P450 DNA Damage DNA strand break Data Development Disease Doxycycline Drug Metabolic Detoxication ERBB2 gene Enzymes Epidemiology Epidermal Growth Factor Receptor Epithelial Cells Estradiol Estriol Estrogen Antagonists Estrogen Metabolism Estrogen Receptors Estrogens Estrone Etiology Exhibits Female Fulvestrant Genes Genetically Engineered Mouse Genomics Goals Hormonal Human Incidence Induced Mutation KRAS2 gene Lead Lung Lung Adenocarcinoma Lung Adenoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Manuscripts Measures Metabolism Methyltransferase Gene Molecular Target Monitor Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Normal tissue morphology Oncogenes Pathologic Patients Phosphorylation Postmenopause Premalignant Cell Prevalence Prevention Prevention strategy Process Production Progesterone Receptor Signaling Reporting Risk Risk Factors Role SCID Mice Smoking Structure of parenchyma of lung TP53 gene Therapeutic Intervention Time Tobacco Tumor Burden Tumor Volume Tumor stage Variant Woman X-Ray Computed Tomography antagonist base bronchial epithelium cancer risk carcinogenicity cell growth cellular engineering design epidemiology study experimental study genotoxicity high risk insight knock-down lung Carcinoma lung cancer prevention lung carcinogenesis lung tumorigenesis male men metaplastic cell transformation mortality mortality risk mutant never smoker non-genomic non-smoker novel preclinical study rate of change receptor-mediated signaling tumor

项目摘要

Project Summary Lung cancer among never-smokers is currently one of the top ten causes of cancer mortality worldwide, with rates more than doubling in the past three decades. Its prevalence in women is consistent with results from epidemiologic and mechanistic studies suggesting that estrogen contributes to lung carcinogenesis. Estrogen can either stimulate cell growth via estrogen receptor (ER)-mediated signaling or be metabolized to genotoxic and mutagenic derivatives; a process that has received little attention. This group is the first to demonstrate the presence of multiple estrogen metabolites in the human lung, including carcinogenic 4-hydroxyestrogen (4- OHE). Preliminary data indicate that the level of 4-OHE is higher in lung tumors vs. adjacent normal tissue from patients with non-small cell lung cancer (NSCLC). Mice deficient in Cyp1b1, the enzyme responsible for 4-OHE production, develop fewer Kras-driven lung adenomas than wild-type controls. However, the mechanism by which 4-OHE promotes lung carcinogenesis remains unknown. The hypothesis of the proposed studies is that 4-OHE, a product of CYP1B1, causes activation of ER signaling and mutation of oncogenes within the lung; processes that increase the risk of lung cancer. Thus, inhibition of CYP1B1 activity could reduce the risk of lung cancer among never-smokers. In Aim 1, immortalized normal human bronchial epithelial cells with variable levels of CYP1B1 and COMT, the rate-limiting estrogen conjugation enzyme, will be employed to assess the ability of 17beta-estradiol or 4-OHE to induce: mutations in genes that drive lung cancer (EGFR, KRAS, p53, ALK, HER2, BRAF, PI3KCA), genomic and nongenomic activities of the ERs, and cellular transformation (anchorage- independent growth and tumor formation in SCID mice). The ability of estrogen metabolites (4-OHE) and ER signaling to cooperate to promote lung tumors formation will be evaluated in Aim 2 in Cyp1b1+/+ or -/- mice carrying a doxycycline-inducible EGFR mutation, in the presence and absence of the ER antagonist fulvestrant. Changes in tumor burden over time will be monitored by CT scans and tumor stage, the profile of pulmonary estrogen metabolites and the phosphorylation status of EGFR and its downstream targets will be determined at necropsy. The estrogen metabolite profile of lung tissue from healthy donors will be established for the first time and compared to that of NSCLC patients (normal tissue) in Aim 3 to determine if pulmonary 4-OHE levels differ in normal tissue from patients and healthy controls and correlate with the activity of CYP1B1 and COMT. The relationship between 4-OHE levels and specific polymorphic variants of CYP1B1 and COMT will also be explored. Data from the proposed studies are anticipated to provide novel insight into the contribution of estrogen metabolism to lung tumorigenesis in never-smokers and reveal the potential utility of CYP1B1 and/or the ERs as molecular targets for the prevention of NSCLC. This promising strategy could ultimately lead to a dramatic reduction in the risk of lung cancer faced by never-smokers worldwide.

项目概要从不吸烟者的肺癌目前是全球十大癌症死亡原因之一，过去三十年里这一比率增加了一倍多。其在女性中的患病率与以下研究结果一致流行病学和机制研究表明雌激素有助于肺癌发生。雌激素可以通过雌激素受体 (ER) 介导的信号传导刺激细胞生长，也可以代谢为基因毒性和诱变衍生物；这个过程很少受到关注。该小组是第一个展示人肺中存在多种雌激素代谢物，包括致癌的 4-羟基雌激素 (4- 哦）。初步数据表明，肺肿瘤中 4-OHE 的水平高于邻近正常组织非小细胞肺癌（NSCLC）患者。缺乏 Cyp1b1（负责 4-OHE 的酶）的小鼠生产中，Kras 驱动的肺腺瘤比野生型对照更少。然而，该机制通过哪种4-OHE促进肺癌发生仍不清楚。拟议研究的假设是 4-OHE 是 CYP1B1 的产物，可引起 ER 信号激活和肺内癌基因突变；增加肺癌风险的过程。因此，抑制 CYP1B1 活性可以降低肺疾病的风险从不吸烟的人患癌症。在目标 1 中，永生化具有不同水平的正常人支气管上皮细胞 CYP1B1 和 COMT（限速雌激素结合酶）将用于评估 17β-雌二醇或 4-OHE 诱导：导致肺癌的基因突变（EGFR、KRAS、p53、ALK、HER2、 BRAF、PI3KCA）、ER 的基因组和非基因组活性以及细胞转化（锚定- SCID 小鼠的独立生长和肿瘤形成）。雌激素代谢物（4-OHE）和ER的能力将在携带 Cyp1b1+/+ 或 -/- 小鼠的 Aim 2 中评估协同促进肺部肿瘤形成的信号传导在存在或不存在 ER 拮抗剂氟维司群的情况下，多西环素诱导的 EGFR 突变。变化随着时间的推移，肿瘤负荷将通过 CT 扫描和肿瘤分期、肺雌激素分布情况进行监测 EGFR 及其下游靶标的代谢物和磷酸化状态将在尸检时确定。将首次建立健康供体肺组织的雌激素代谢谱与目标 3 中的 NSCLC 患者（正常组织）进行比较，以确定肺 4-OHE 水平是否存在差异来自患者和健康对照的正常组织，并与 CYP1B1 和 COMT 的活性相关。这 4-OHE 水平与 CYP1B1 和 COMT 的特定多态性变体之间的关系也将是探索过。拟议研究的数据预计将为雌激素的贡献提供新的见解从不吸烟者的代谢与肺部肿瘤发生的关系，并揭示 CYP1B1 和/或 ER 的潜在用途作为预防 NSCLC 的分子靶点。这一充满希望的策略最终可能会带来戏剧性的结果降低全世界从不吸烟者患肺癌的风险。