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

• 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
• 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

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.

项目摘要 不吸烟者中的肺癌目前是全球癌症死亡率的十大原因之一， 在过去的三十年里增长了一倍多。其在女性中的流行率与以下结果一致： 流行病学和机制研究表明雌激素有助于肺癌的发生。雌激素 可通过雌激素受体（ER）介导的信号传导刺激细胞生长，或代谢为遗传毒性 和诱变衍生物;一个很少受到关注的过程。这个小组是第一个展示 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- OHE）。初步数据表明，肺肿瘤中4-OHE的水平高于肺肿瘤周围的正常组织。 非小细胞肺癌（NSCLC）患者。缺乏Cyp 1b 1（负责4-OHE的酶）的小鼠 与野生型对照相比，Kras驱动的肺腺瘤较少。然而， 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CYP 1B 1的一种产物，引起ER信号的激活和肺内癌基因的突变; 肺癌的早期症状有哪些？因此，抑制CYP 1B 1活性可以降低肺损伤的风险。 不吸烟者的癌症在目标1中，永生化的正常人支气管上皮细胞具有不同水平的 CYP 1B 1和COMT，限速雌激素结合酶，将被用来评估的能力， 17 β-雌二醇或4-OHE诱导：驱动肺癌的基因突变（EGFR，KRAS，p53，ALK，HER 2， BRAF，PI 3 KCA），ER的基因组和非基因组活性，以及细胞转化（锚定- 在SCID小鼠中独立生长和肿瘤形成）。雌激素代谢产物（4-OHE）和ER 将在Aim 2中在携带Cyp 1b 1 +/+或-/-小鼠中评价协同促进肺肿瘤形成的信号传导 在存在和不存在ER拮抗剂氟维司群的情况下，多西环素诱导的EGFR突变。变化 肿瘤负荷随时间的变化将通过CT扫描和肿瘤分期、肺雌激素的分布来监测 将在尸检时确定EGFR及其下游靶标的代谢物和磷酸化状态。 将首次建立健康供体肺组织的雌激素代谢物谱， 与目的3中的NSCLC患者（正常组织）相比，以确定肺4-OHE水平是否与目的3中的NSCLC患者（正常组织）不同。 正常组织和健康对照，并与CYP 1B 1和COMT的活性相关。的 还将研究4-OHE水平与CYP 1B 1和COMT特异性多态性变体之间的关系。 探讨了预计拟议研究的数据将为雌激素的贡献提供新的见解 在不吸烟者中，CYP 1B 1和/或ER代谢与肺肿瘤发生的关系，并揭示了CYP 1B 1和/或ER的潜在效用。 作为预防NSCLC的分子靶点。这一有希望的战略最终可能导致一场戏剧性的 降低全世界从不吸烟者面临的肺癌风险。