Combinatorial epigenetic-based prevention of breast cancer

基于表观遗传学的组合预防乳腺癌

• 批准号: 8694750
• 负责人: TRYGVE O TOLLEFSBOL
• 金额: $ 29.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694750
• 关键词: Address; Affect; Apoptosis; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Broccoli - dietary; Cancer Etiology; Cancerous; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Consumption; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Diagnosis; Diet; Dose; Down-Regulation; Epigallocatechin Gallate; Epigenetic Process; Estrogen Receptors; Estrogen receptor negative; Event; Gene Expression Regulation; Genes; Genomics; Goals; Growth; Health; High Risk Woman; Histone Acetylation; Histone Deacetylase; Human; In Vitro; Individual; Investigation; Laboratories; Lead; Malignant Neoplasms; Morbidity - disease rate; Mus; Normal Cell; Pathogenesis; Pathology; Pathway interactions; Play; Predisposition; Regulation; Role; Solutions; Sulforaphane; System; Tamoxifen; Techniques; Technology; Telomerase; Tumor Suppressor Genes; Tumor Suppressor Proteins; Woman; base; bisulfite; carcinogenesis; chromatin immunoprecipitation; combinatorial; cost effectiveness; epigenetic marker; epigenomics; gallocatechol; high risk; in vivo; malignant breast neoplasm; mortality; novel; outcome forecast; prevent; promoter; public health relevance; response; tumor; tumor growth

DESCRIPTION (provided by applicant): The conventional use of single-agent dietary approaches to prevent breast cancer (BC) can have limitations in that these compounds may not be sufficiently efficacious when acting alone to reliably prevent BC or they may require impractical or unsafe levels of consumption to acquire significant efficacy. A solution to this challenge is combinatorial approaches allowing reduced doses of the individual natural compounds that, in combination, render greater efficacy. We have shown that combined green tea polyphenols (GTPs) and sulforaphane (SFN)-enriched broccoli sprouts (BSp) administered at safe levels consumable by humans are highly effective in preventing BC tumors in mice that spontaneously develop BC. Our results indicate that the efficacy of this combinatorial dietary approach of GTPs and BSp depends on the ability of these natural dietary products to significantly impact epigenetic gene regulation. We hypothesize that combined GTPs and BSp are highly effective in neutralizing epigenetic aberrations of key tumor-related genes in BC as well as epigenomic alterations and that this combinatorial dietary approach allows less consumption of these dietary products to render a greater impact in preventing BC. These investigations are important for a number of reasons. First, it is important to elucidate the impac and mechanisms of this combinatorial dietary epigenetic approach and its effects on the epigenetics of key tumor-related genes since little is known about the combined epigenetic effects of these dietary products. Second, it is also important because we do not yet know the global profile of the epigenetic effects of these compounds and what other genes may be impacted by these compounds. Third, we do not yet fully understand what impact the combination of these compounds will have on BC tumors of different origins and pathways of carcinogenesis. Finally, there are few options for women who develop estrogen receptor-negative [ER(-)] BC and we have found that combined GTPs and BSp is highly effective in converting ER(-) tumors to ER(+) tumors that can be readily prevented with tamoxifen (TAM). It will therefore be important to more fully understand the mechanisms and efficacy of these combinatorial approaches in preventing ER(-) BC. A goal of this proposal is to confront these challenges through the use of novel techniques we have invented such as chromatin immunoprecipitation (ChIP)-genomic bisulfite sequencing (GBS) or ChIP-GBS and advanced epigenomic technologies. The impact of this proposed investigation will be significant since hundreds of thousands of women worldwide are affected by BC. The use of safe and effective combinations of epigenetic aberration-neutralizing dietary compounds has high translational potential for preventing BC by providing lower doses of these compounds, enhanced efficacy and greater cost effectiveness. There is also a need for identification of epigenetic biomarkers of BC that will aid in the predisposition, diagnosis and prognosis of BC. Finally, the proposed study will provide hope for women who are at high risk of developing highly lethal ER(-) BC and who have few options.

描述（由申请人提供）：常规使用单药饮食方法预防乳腺癌（BC）可能会有局限性，因为这些化合物在单独起作用以可靠地防止BC时可能不够有效，否则它们可能需要不切实际或不安全的消费水平才能获得显着功效。解决这一挑战的一种解决方案是组合方法，允许减少各个自然化合物的剂量，从而结合起来，从而提高了功效。我们已经表明，在人类易于的安全水平上给药的绿茶多酚（GTP）和硫磺烷（SFN）富含的西兰花芽（BSP）在自发发展BC的小鼠中非常有效。我们的结果表明，GTP和BSP的这种组合饮食方法的功效取决于这些天然饮食产物显着影响表观遗传基因调控的能力。我们假设联合GTP和BSP在中和卑诗省关键肿瘤相关基因的表观遗传畸变以及表观基因组改变方面非常有效，并且这种组合饮食方法可以减少对这些饮食产物的消耗，从而在预防BC中产生更大的影响。这些调查很重要，原因有很多。首先，重要的是要阐明这种组合饮食表观遗传学方法的含量和机制及其对关键肿瘤相关基因表观遗传学的影响，因为对这些饮食产物的表观遗传效应知之甚少。其次，这也很重要，因为我们尚不知道这些化合物的表观遗传效应的全球特征以及这些化合物可能影响哪些其他基因。第三，我们尚未完全了解这些化合物的组合将对不同起源和癌变途径的BC肿瘤产生什么影响。最后，对于开发雌激素受体阴性[ER（ - ）] BC的女性几乎没有选择，我们发现GTPS和BSP的组合在将ER（ - ）肿瘤转化为ER（+）肿瘤方面非常有效，可以用他莫昔芬（Tamoxifen）（TAM）轻松防止ER（+）肿瘤。因此，更重要的是要更充分地了解这些组合方法在防止ER（ - ）BC中的机制和功效。该提案的一个目的是通过使用我们发明的新技术来应对这些挑战，例如染色质免疫沉淀（CHIP） - 基因组基硫酸盐测序（GBS）或芯片GB和高级表观基因组技术。这项拟议的调查的影响将很大，因为全世界成千上万的妇女受到卑诗省的影响。通过提供较低剂量的这些化合物，增强的疗效和更大的成本效率，使用表观遗传像差中和饮食化合物的安全有效组合具有很高的转化潜力。还需要鉴定表观遗传生物标志物 BC将有助于BC的易感性，诊断和预后。最后，拟议的研究将为患有高度致命的ER（ - ）且几乎没有选择的妇女提供希望。