Molecular Mechanisms & Importance of Oxidative Stress in Estrogen-Induced Carcino

分子机制

• 批准号: 7280311
• 负责人: HARI K BHAT
• 金额: $ 28.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7280311
• 关键词: 17p; 4-OH-E(2); 8-hydroxy-2' -deoxyguanosine; Address; Affinity; Animal Model; Animals; Antioxidants; Ascorbic Acid; Awareness; Binding; Biological Models; Breast; Butylated Hydroxyanisole; Carcinogens; Catechol Estrogens; Catechols; Cell Line; Cell Proliferation; Cells; Chemicals; Complementary DNA; Complex; Condition; Cytochrome P450; Data; Development; Doctor of Philosophy; Early treatment; Enzyme Inhibition; Enzymes; Epithelial Cells; Estradiol; Estrogen Antagonists; Estrogen Metabolism; Estrogen Receptor 2; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Event; Exposure to; Female; Free Radicals; Gene Expression; Gene Expression Regulation; Gene Silencing; Generations; Genes; Goals; Histopathology; Human; ICI 182780; In Vitro; Inbred ACI Rats; Incidence; Knock-out; Length; Lipid Peroxidation; Liver; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Manganese Superoxide Dismutase; Mediating; Messenger RNA; Metabolic Activation; Modeling; Molecular; Neoplasms; Organ; Outcome Measure; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phase; Play; Process; Production; Prostaglandins; Proteins; Publishing; Purpose; Quinones; Rattus; Reactive Oxygen Species; Regulation; Research Personnel; Response Elements; Role; Signal Transduction; Specific qualifier value; Stress; Superoxide Dismutase; TFF1 gene; Tamoxifeni Citras; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Vitamin K 3; benzoquinone; c-myc Genes; carcinogenesis; catalase; glutathione peroxidase; in vivo; in vivo Model; inhibitor/antagonist; innovation; knockout gene; malignant breast neoplasm; neoplastic; prevent; programs; research study; treatment duration; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Prolonged exposure to estrogens is actively involved in the development of breast cancers. Available data suggest that the mechanism behind the formation of tumors by estrogens is complex and not well understood. An important part in estrogen-induced carcinogenesis is the growing awareness that reactive oxygen species may serve as signaling agents in carcinogenic pathways. The proposed study seeks to establish the molecular mechanism(s) underlying the role of oxidative stress in estrogen-induced carcinogenesis in an animal model relevant to human breast cancers - namely, the female ACI rat model of estrogen-induced breast cancer - and, by using the human breast epithelial cell line MCF-10F, thus establish the importance of oxidative stress in estrogen-induced breast cancer. Therefore, the investigators will characterize: the role of estrogen metabolism-mediated oxidative stress (Specific Aim 1); the role of estrogen receptors (ERs) in the generation of oxidative stress (Specific Aim 2); the role of oxidative stress in modifying ER-dependent gene regulation (Specific Aim 3); and, the role cytochrome P450 1B1 in estrogen-induced oxidative stress and subsequent carcinogenesis (Specific Aim 4). To accomplish Specific Aims 1-4, rats will be treated with estrogens, anti-estrogens, antioxidants, or with inhibitors of metabolic activation. In in vitro approaches, MCF-10F cells will be genetically manipulated with gene insertions and gene knockouts. These cell lines will then be treated with estrogens, anti-estrogens, antioxidants or inhibitors of metabolic activation to study the roles of estrogen receptors and antioxidant defense genes in the regulation of estrogen-dependent oxidant stress. Treatment of animals will be for seven months and information obtained from groups of animals that have been sacrificed at earlier times will be used to study changes during early treatment periods, as well as during both preneoplastic and neoplastic phases of development. Tumor incidence and histopathology will be characterized. Markers of oxidative stress as well as levels of antioxidant defense enzymes will be quantified both in the target organ breast and the nontarget organ liver; also, expression and regulation of estrogen-estrogen receptor-dependent genes will be quantified. Given the federal register's recent inclusion of estrogens as human carcinogens, the proposed studies have a great potential in the development of therapeutic strategies for the treatment of estrogen-induced neoplasia.

描述（由申请人提供）：长期暴露于雌激素与乳腺癌的发展密切相关。现有的数据表明，雌激素形成肿瘤的机制是复杂的，并没有得到很好的理解。在雌激素诱导的癌变中，一个重要的部分是人们越来越意识到活性氧可能在致癌途径中作为信号剂。本研究拟在与人乳腺癌相关的动物模型——雌性ACI大鼠雌激素诱导乳腺癌模型中，建立氧化应激在雌激素诱导乳腺癌中作用的分子机制，并利用人乳腺上皮细胞系MCF-10F，从而确立氧化应激在雌激素诱导乳腺癌中的重要性。因此，研究人员将描述：雌激素代谢介导的氧化应激的作用（Specific Aim 1）；雌激素受体（er）在氧化应激产生中的作用（Specific Aim 2）；氧化应激在改变er依赖性基因调控中的作用（Specific Aim 3）；细胞色素P450 1B1在雌激素诱导的氧化应激和随后的癌变中的作用（Specific Aim 4）。为了实现特定目标1-4，大鼠将接受雌激素、抗雌激素、抗氧化剂或代谢激活抑制剂的治疗。在体外方法中，MCF-10F细胞将通过基因插入和基因敲除进行基因操作。然后用雌激素、抗雌激素、抗氧化剂或代谢激活抑制剂处理这些细胞系，以研究雌激素受体和抗氧化防御基因在雌激素依赖性氧化应激调节中的作用。动物的治疗将持续7个月，从早期被牺牲的动物群体中获得的信息将用于研究早期治疗期间以及肿瘤前和肿瘤发展阶段的变化。肿瘤发生率和组织病理学将被描述。靶器官乳房和非靶器官肝脏中的氧化应激标志物以及抗氧化防御酶水平将被量化；此外，雌激素-雌激素受体依赖基因的表达和调控将被量化。鉴于联邦公报最近将雌激素列为人类致癌物，拟议的研究在发展治疗雌激素诱导肿瘤的治疗策略方面具有很大的潜力。