CYP1B1: A Molecular Target for Chemoprevention of Lung Adenocarcinoma

CYP1B1：肺腺癌化学预防的分子靶点

• 批准号: 8538327
• 负责人: MARGIE L. CLAPPER
• 金额: $ 8.39万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538327
• 关键词: Age; Alleles; Animal Model; Antiestrogen Therapy; Attention; Benzo(a)pyrene; CYP1A1 gene; Cancer Etiology; Cancer Patient; Carcinogens; Catechol O-Methyltransferase; Cessation of life; Chemoprevention; Chemopreventive Agent; Cytochrome P450; Data; Development; Diagnostic Neoplasm Staging; Disease; Enzymes; Epidemic; Epidemiologic Studies; Estradiol; Estriol; Estrogen Metabolism; Estrogen Receptors; Estrogens; Estrone; Exposure to; Female; Future; Gene Deletion; Gene Expression; Genes; Genetic; Glutathione S-Transferase; Goals; Grant; Growth; High Pressure Liquid Chromatography; Human; Incidence; Lead; Lesion; Lung; Lung Adenocarcinoma; Lung Neoplasms; Magnetic Resonance Imaging; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Modeling; Molecular Profiling; Molecular Target; Morbidity - disease rate; Mus; Mutagens; Mutation; NQO1 gene; Normal tissue morphology; Pathway interactions; Premalignant; Prevention Research; Process; Production; Quinones; Research; Resveratrol; Role; Signal Pathway; Smoke; Structure of parenchyma of lung; Testing; Therapeutic; Time; Tobacco smoke; Transcript; Transferase; Transgenic Organisms; Tumor Burden; Tumor Volume; Tumor stage; Variant; Woman; analog; base; cancer prevention; cancer risk; cancer therapy; carcinogenesis; clinically relevant; inhibitor/antagonist; insight; liquid chromatography mass spectrometry; lung cancer prevention; lung carcinogenesis; lung tumorigenesis; mRNA Expression; male; malignant breast neoplasm; men; mortality; mouse model; non-smoker; novel; novel therapeutic intervention; prevent; programs; receptor; receptor-mediated signaling; response; sulfotransferase; tumor; tumor progression

DESCRIPTION (provided by applicant): Lung cancer remains the leading cause of cancer death among men and women in the U.S., with rates in women increasing 6-fold in recent decades. Furthermore, the majority of lung cancer cases in nonsmokers occur in women. Results from several epidemiological studies suggest that, in addition to tobacco smoke, estrogen may contribute to lung cancer risk and progression. Although receptor-mediated signaling pathways have been well studied in carcinogenesis, much less attention has been given to the potential contribution of estrogen metabolizing enzymes to tumor formation and progression. The goal of the present study is to use novel animal models to assess the impact of alterations in estrogen metabolism on lung cancer development. Rationale for this experimentation is provided by preliminary data that indicate for the first time that estrogen is metabolized within murine lung tissue. Exposure of mice to tobacco smoke induces the expression of cytochrome P450 1B1 (CYP1B1), an enzyme that converts both estrogen and constituents of tobacco smoke to carcinogenic derivatives. CYP1B1 expression is elevated in lung tumors vs. adjacent normal tissue, and levels of 4-hydroxyestrogen (4-OHE), a genotoxic estrogen metabolite produced primarily by CYP1B1, are elevated significantly within the murine lung following smoke exposure. The hypothesis of the proposed study is that inhibition of CYP1B1 will lead to decreased production of 4-OHE and provide protection against lung cancer; thus representing a novel molecular target for the chemoprevention of this disease. This hypothesis will be tested using the clinically relevant LSL-KrasG12D mouse model of lung tumorigenesis, CYP1B1-/- mice and novel double transgenic LSL- KrasG12D/CYP1B1-/- mice that have been established recently by this group. The impact of CYP1B1 deletion on estrogen metabolism within the lung will be examined in Specific Aim 1 by comparing the expression of genes involved in estrogen metabolism and estrogen metabolite profiles in lung tissue of female CYP1B1-/- and CYP1B1+/+ mice. In Aim 2, the feasibility of inhibiting CYP1B1 as a strategy for lung cancer prevention will be investigated using the LSL-KrasG12D mouse model. Inhibition of CYP1B1 will be achieved by gene deletion or administration of 2,3',4,5'-tetramethoxystilbene (TMS), a synthetic analog of resveratrol that is a selective inhibitor of CYP1B1. The effects of CYP1B1 inhibition on change in total tumor burden (tumor volume as determined by MRI) and tumor stage will be determined. Data obtained from the proposed studies are anticipated to reveal the potential utility of CYP1B1 as a molecular target for chemoprevention and provide novel insight into the contribution of estrogen metabolism to lung cancer development.

描述（由申请人提供）：肺癌仍然是美国男性和女性癌症死亡的主要原因，近几十年来，女性的发病率增加了6倍。此外，非吸烟者中的大多数肺癌病例发生在女性中。几项流行病学研究的结果表明，除了烟草烟雾外，雌激素可能会导致肺癌的风险和进展。虽然受体介导的信号通路在肿瘤发生中已经得到了很好的研究，但很少关注雌激素代谢酶对肿瘤形成和进展的潜在贡献。本研究的目的是使用新的动物模型来评估雌激素代谢的改变对肺癌发展的影响。初步数据首次表明雌激素在鼠肺组织内代谢，提供了该实验的基本原理。小鼠暴露于烟草烟雾诱导细胞色素P450 1B 1（CYP 1B 1）的表达，细胞色素P450 1B 1是一种将雌激素和烟草烟雾成分转化为致癌衍生物的酶。与邻近的正常组织相比，肺肿瘤中CYP 1B 1表达升高，并且在烟雾暴露后，鼠肺中4-羟基雌激素（4-OHE）（主要由CYP 1B 1产生的遗传毒性雌激素代谢物）的水平显著升高。拟议研究的假设是，抑制CYP 1B 1将导致4-OHE的产生减少，并提供对肺癌的保护;因此代表了这种疾病的化学预防的新分子靶点。将使用临床相关的肺肿瘤发生LSL-KrasG 12 D小鼠模型、CYP 1B 1-/-小鼠和该研究组最近建立的新型双转基因LSL-KrasG 12 D/CYP 1B 1-/-小鼠来检验该假设。在特定目的1中，将通过比较雌性CYP 1B 1-/-和CYP 1B 1 +/+小鼠肺组织中参与雌激素代谢的基因表达和雌激素代谢产物谱，检查CYP 1B 1缺失对肺内雌激素代谢的影响。在目的2中，将使用LSL-KrasG 12 D小鼠模型研究抑制CYP 1B 1作为肺癌预防策略的可行性。CYP 1B 1的抑制将通过基因缺失或给予2，3 '，4，5'-四甲氧基芪（TMS）来实现，TMS是白藜芦醇的合成类似物，是CYP 1B 1的选择性抑制剂。将确定CYP 1B 1抑制对总肿瘤负荷（通过MRI测定的肿瘤体积）和肿瘤分期变化的影响。从拟议的研究中获得的数据预计将揭示CYP 1B 1作为化学预防的分子靶点的潜在效用，并提供新的见解雌激素代谢对肺癌发展的贡献。