Prevention of estrogen-mediated mammary carcinogenesis by mixtures of tocopherols

说明(申请人提供)：生育酚是天然存在的酚类化合物，是人体内维生素E的主要形式。生育酚以四种形式存在，分别为α(？)、β(？)、γ(？)和Delta(？)。最近对生育酚的临床试验在预防癌症方面的结果令人失望。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了解不足而设计的。迫切需要调查该组织的活动。 不同的形式，如？-生育酚，美国饮食中维生素E的主要形式，并用于确定生育酚的分子机制和靶点。我们最近的研究表明，在乳腺癌动物模型中，富含生育酚(？-TMT)的生育酚混合物可以抑制乳腺增生的进展，诱导体内和细胞系的细胞凋亡，并防止乳腺肿瘤的发生。我们假设生育酚抑制氧化/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？)信号转导，抑制细胞增殖，诱导细胞凋亡，从而抑制乳腺癌的发生。我们打算通过四个具体的目标来验证我们的假设并实现我们的目标：1.研究天然生育酚混合物？-TMT对雌激素诱导的ACI大鼠乳腺癌模型的增殖和肿瘤形成的抑制作用，并呈剂量依赖关系。2.纯化单独的生育酚(T)、β-T、β-T和β-T，并测定其在雌激素诱导的急性脑梗塞大鼠乳腺肿瘤形成中的防癌活性。3.阐明生育酚调节雌激素受体(ER)和PPAR？，从而抑制细胞增殖和细胞存活的分子机制。4.探讨生育酚抑制氧化/亚硝化应激的分子机制，以及核因子-E2相关因子-2(NRF2)的可能参与。生育酚通常存在于植物油中，很容易作为膳食补充剂使用。了解自然产生的生育酚混合物和单独的生育酚的影响，并确定关键的作用机制，对于使用它们预防癌症至关重要。我们的数据将对未来的研究选择最优形式或 生育酚的混合物，以及为人类乳腺癌预防试验设计更好的方案。这项研究将首次对生育酚混合物和单独的生育酚预防乳腺癌进行全面评估。

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.