Tocopherol-mediated inhibition of breast carcinogenesis

生育酚介导的乳腺癌抑制作用

• 批准号: 7747368
• 负责人: Nanjoo Suh
• 金额: $ 7.73万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747368
• 关键词: Achievement; Animal Cancer Model; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Attention; Biomedical Technology; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Treatment; Cancer Patient; Cancer cell line; Cell Line; Cell Proliferation; Chemopreventive Agent; Colon Carcinoma; Cottonseed; Data; Diagnosis; Diet; Dinoprostone; ERBB2 gene; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Estrogen Receptor 2; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Food; Future; Health Benefit; High Risk Woman; Human; Immunohistochemistry; Incidence; Inflammation; Isomerism; Laboratories; Leukotriene B4; Literature; Malignant Neoplasms; Mammary gland; Mastectomy; Measures; Mediating; Methylnitrosourea; Molecular; Molecular Mechanisms of Action; Mus; New Agents; Nuclear Receptors; Outcome; Oxidative Stress; Patients; Peroxisome Proliferator-Activated Receptors; Pre-Clinical Model; Prevention; Preventive; Property; Protein Isoforms; Public Health; Rattus; Receptor Signaling; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Safety; Signal Pathway; Soybeans; Staging; Technology; Testing; Time; Tissues; Tocopherols; Tocotrienols; Transgenic Mice; Translations; United States; Vegetable Oils; Vitamin E; Western Blotting; Woman; alpha Tocopherol; base; breast lumpectomy; cancer prevention; carcinogenesis; disorder prevention; in vivo; isoprostaglandin F2alpha type-III; malignant breast neoplasm; molecular marker; mortality; pre-clinical; preclinical study; prevent; response; tumor

DESCRIPTION (provided by applicant): Recent biomedical technology advances have made it possible to detect breast cancer earlier, but options currently available to help patients with primary breast cancer or women at high risk of breast cancer are very limited. The long-term objective of our project is to identify and develop safe and efficacious agents, such as tocopherols, for prevention of breast cancer. Tocopherols are lipophilic phenolic antioxidants present in significant amounts in vegetable oils, such as soybean, corn, canola and cottonseed. Our laboratory has found that mixed tocopherols containing mainly gamma- and delta-tocopherols prevent an estrogen receptor (ER)- positive breast cancer. Based on our preliminary studies, we hypothesize that gamma- and delta-tocopherols, not alpha-tocopherol (known as a classic vitamin E), prevent breast cancer by inhibiting cell proliferation, inflammation, and oxidative stress, and by regulating receptor signaling pathways including peroxisome proliferator activated receptor (PPAR), ER and Her-2. The major specific aims of this project are to characterize the cancer preventive activities of mixed tocopherols as well as pure isoforms of tocopherols since it is not clear which tocopherol isomers are responsible for chemopreventive effects against breast cancer. Using two distinct preclinical models of breast cancer, we will determine the preventive efficacy of mixed tocopherols as well as the pure alpha-, gamma- and delta-tocopherols in an estrogen receptor (ER)-positive breast cancer and in an ER-negative/Her-2 positive breast cancer. Using immunohistochemistry, ELISA, Western Blot analysis and real time RT-PCR, we will investigate the efficacy and safety of tocopherols in animal models of breast cancer, analyze molecular markers and identify the mechanism of action of tocopherols in vivo. The proposed study will determine (a) the preventive efficacy of mixed tocopherols and the pure alpha-, gamma- and delta tocopherols individually in an ER-positive breast cancer model, (b) the preventive efficacy of mixed tocopherols and the pure alpha-, gamma- and delta tocopherols individually in a Her-2 positive breast cancer model using MMTV-Her-2/neu transgenic mice, and (c) the molecular mechanisms of the tocopherols in receptor signaling pathways such as PPAR, ER and Her-2. This project will provide a thorough understanding of cancer preventive activities of different tocopherols and their combinations, elucidate the detailed molecular mechanisms of cancer preventive actions on tocopherols, and provide fundamental information of tocopherols for future human breast cancer prevention studies.

描述（由申请人提供）： 最近的生物医学技术进步使早期发现乳腺癌成为可能，但目前可用于帮助原发性乳腺癌患者或乳腺癌高危妇女的选择非常有限。我们项目的长期目标是确定和开发安全有效的药物，如生育酚，用于预防乳腺癌。生育酚是亲脂性酚类抗氧化剂，以显著量存在于植物油如大豆、玉米、卡诺拉和棉籽中。我们的实验室发现，主要含有γ-和δ-生育酚的混合生育酚可预防雌激素受体（ER）阳性乳腺癌。基于我们的初步研究，我们假设γ-和δ-生育酚，而不是α-生育酚（称为经典的维生素E），通过抑制细胞增殖，炎症和氧化应激，并通过调节受体信号传导途径，包括过氧化物酶体增殖物激活受体（PPAR），ER和Her-2来预防乳腺癌。该项目的主要具体目标是描述混合生育酚以及生育酚纯异构体的癌症预防活性，因为尚不清楚哪种生育酚异构体对乳腺癌具有化学预防作用。使用两种不同的乳腺癌临床前模型，我们将确定混合生育酚以及纯α-、γ-和δ-生育酚在雌激素受体（ER）阳性乳腺癌和ER阴性/Her-2阳性乳腺癌中的预防功效。本研究将采用免疫组化、ELISA、Western Blot分析和真实的时间RT-PCR等方法，研究生育酚在乳腺癌动物模型中的有效性和安全性，分析其分子标志物，并确定其体内作用机制。所提出的研究将确定（a）混合生育酚和纯α-、γ-和δ-生育酚单独在ER阳性乳腺癌模型中的预防功效，（B）混合生育酚和纯α-、γ-和δ-生育酚单独在Her-2阳性乳腺癌模型中使用MMTV-Her-2/neu转基因小鼠的预防功效，以及（c）生育酚在受体信号传导途径如PPAR、ER和Her-2中的分子机制。本项目将深入了解不同生育酚及其组合的癌症预防作用，阐明生育酚预防癌症的详细分子机制，并为未来的人类乳腺癌预防研究提供基础信息。