Prevention of estrogen-mediated mammary carcinogenesis by mixtures of tocopherols

通过生育酚混合物预防雌激素介导的乳腺癌发生

• 批准号: 8704881
• 负责人: Nanjoo Suh
• 金额: $ 37.65万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704881
• 关键词: Address; Animal Model; Antioxidants; Apoptosis; Biological Markers; Blood; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Prevention Trial; Breast Carcinogenesis; Cell Line; Cell Proliferation; Cell Survival; Clinical Trials; Conflict (Psychology); Data; Diet; Dosage Forms; Dose; Effectiveness; Estrogen Receptors; Estrogens; Evaluation; Food; Future; General Population; Human; Hyperplasia; In Vitro; Inbred ACI Rats; Individual; Intervention Studies; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Methods; Molecular; Molecular Mechanisms of Action; NF-E2-related factor 2; Outcome; Peroxisome Proliferator-Activated Receptors; Prevention; Preventive; Protocols documentation; Receptor Signaling; Research; Signal Pathway; Signal Transduction; System; Testing; Tissues; Tocopherols; Vegetable Oils; Vitamin E; alpha Tocopherol; base; cancer prevention; design; dietary supplements; in vivo; malignant breast neoplasm; nitrosative stress; prevent; response; stem; tumorigenesis

DESCRIPTION (provided by applicant): Tocopherols are naturally occurring phenolic compounds and are the major forms of vitamin E in our body. Tocopherols exist in four forms, designated as alpha (¿), beta (¿), gamma (?), and delta (¿). Recent clinical trials with ¿-tocopherol have provided disappointing results for cancer prevention. We believe these studies were designed based on insufficient knowledge of the cancer preventive activities of the different forms of the tocopherols. There is an urgent need for investigating the activities of the different forms, such as ?-tocopherol, the major form of vitamin E in the diet in the U.S, and for identifying molecular mechanisms and targets of tocopherols. Our recent studies demonstrate that tocopherol mixtures that are rich in ?-tocopherol (?-TmT) inhibit progression of mammary hyperplasia and induce apoptosis in vivo and in cell lines, and prevent mammary tumorigenesis in animal models of breast cancer. We hypothesize that ?- and ¿-tocopherols suppress oxidative/nitrosative stress, modulate estrogen receptor (ER) and peroxisome proliferator-activated receptor-? (PPAR?) signaling, inhibit cell proliferation and induce apoptosis, resulting in the inhibition of breast carcinogenesis. We propose to test our hypotheses and achieve our objectives by addressing four Specific Aims: 1. Investigate the dose-dependent inhibitory effects of a naturally occurring tocopherol mixture ?-TmT on estrogen-induced hyperplasia and tumorigenesis in the ACI rat model of mammary cancer. 2. Purify individual tocopherols (T), ?-T, ¿-T, and ¿-T, and determine their cancer preventive activities in estrogen-mediated mammary tumorigenesis in ACI rats. 3. Elucidate the molecular mechanisms of action of tocopherols in modulating estrogen receptors (ERs) and PPAR?, resulting in suppressing cell proliferation and cell survival in cell lines. 4. Investigate the molecular mechanisms of action of tocopherols in suppressing oxidative/nitrosative stress, and the possible involvement of NF-E2 related factor-2 (Nrf2). Tocopherols are commonly occurring in vegetable oils and readily available as dietary supplements. Understanding the effects of naturally occurring tocopherol mixtures and individual tocopherols and identifying the key mechanisms of action is critical for their use in prevention of cancer. Our data will be valuable for future studies in selecting the optimal form or mixtures of tocopherols and in designing better protocols for human breast cancer prevention trials. This study will provide the first comprehensive evaluation of tocopherol mixtures and individual tocopherols for the prevention of breast cancer.

描述（由申请人提供）：生育酚是天然存在的酚类化合物，是我们体内维生素E的主要形式。生育酚以四种形式存在，称为α（<$）、β（<$）、γ（？）delta（？）最近关于生育酚的临床试验为癌症预防提供了令人失望的结果。我们认为，这些研究是基于对不同形式生育酚的癌症预防活性的认识不足而设计的。目前迫切需要调查这些组织的活动， 不同的形式，如？生育酚是美国饮食中维生素E的主要形式，并用于鉴定生育酚的分子机制和靶点。我们最近的研究表明，生育酚混合物，富含？-生育酚（？- TmT）在体内和细胞系中抑制乳腺增生的进展并诱导细胞凋亡，并在乳腺癌动物模型中预防乳腺肿瘤发生。我们假设？-和<$-生育酚抑制氧化/亚硝化应激，调节雌激素受体（ER）和过氧化物酶体增殖物激活受体-？(PPAR?)信号传导，抑制细胞增殖并诱导细胞凋亡，从而抑制乳腺癌的发生。我们建议通过解决四个具体目标来测试我们的假设并实现我们的目标：1.研究天然存在的生育酚混合物的剂量依赖性抑制作用？TmT对ACI大鼠乳腺癌模型中雌激素诱导的增生和肿瘤发生的影响。2.纯化单个生育酚（T），T，<$-T，和<$-T，并确定其在ACI大鼠雌激素介导的乳腺肿瘤发生中的癌症预防活性。3.阐明生育酚调节雌激素受体（ER）和PPAR？的分子作用机制，导致抑制细胞系中的细胞增殖和细胞存活。4.研究生育酚在抑制氧化/亚硝化应激中的分子作用机制，以及NF-E2相关因子-2（Nrf 2）的可能参与。生育酚通常存在于植物油中，并且很容易作为膳食补充剂获得。了解天然存在的生育酚混合物和单个生育酚的作用并确定其关键作用机制对于其用于预防癌症至关重要。我们的数据将是有价值的，为今后的研究，在选择最佳的形式或 生育酚的混合物和设计更好的人类乳腺癌预防试验方案。这项研究将首次全面评估生育酚混合物和单个生育酚对乳腺癌的预防作用。