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: 8829200
• 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/8829200
• 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 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 sequencing; carcinogenesis; chromatin immunoprecipitation; combinatorial; cost effectiveness; dietary approach; epigenetic marker; epigenomics; gallocatechol; high risk; in vivo; malignant breast neoplasm; mortality; novel; outcome forecast; prevent; promoter; 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）：传统使用单药饮食方法预防乳腺癌 (BC) 可能存在局限性，因为这些化合物单独作用以可靠地预防 BC 时可能不够有效，或者它们可能需要不切实际或不安全的水平的消耗以获得显着的功效。应对这一挑战的一个解决方案是组合方法，允许减少单个天然化合物的剂量，组合起来可以产生更大的功效。我们已经证明，以人类可食用的安全水平施用绿茶多酚 (GTP) 和富含萝卜硫素 (SFN) 的西兰花芽 (BSp) 可以非常有效地预防自发发展为 BC 的小鼠的 BC 肿瘤。我们的结果表明，这种 GTP 和 BSp 组合饮食方法的功效取决于这些天然饮食产品显着影响表观遗传基因调控的能力。我们假设组合的 GTP 和 BSp 在中和 BC 中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这些饮食产品的消耗，从而对预防 BC 产生更大的影响。由于多种原因，这些调查很重要。首先，阐明这种组合饮食表观遗传学方法的影响和机制及其对关键肿瘤相关基因表观遗传学的影响非常重要，因为人们对这些饮食产品的组合表观遗传学效应知之甚少。其次，这也很重要，因为我们还不知道这些化合物的表观遗传效应的总体概况，以及哪些其他基因可能受到这些化合物的影响。第三，我们尚未完全了解这些化合物的组合会对不同起源和致癌途径的 BC 肿瘤产生什么影响。最后，对于患有雌激素受体阴性 [ER(-)] BC 的女性来说，几乎没有什么选择，我们发现联合 GTP 和 BSp 在将 ER(-) 肿瘤转化为 ER(+) 肿瘤方面非常有效，并且可以很容易地用他莫昔芬（TAM）预防。因此，更全面地了解这些组合方法预防 ER(-) BC 的机制和功效非常重要。该提案的目标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)-基因组亚硫酸氢盐测序 (GBS) 或 ChIP-GBS 以及先进的表观基因组技术。这项拟议调查的影响将是巨大的，因为全世界有数十万女性受到 BC 的影响。使用安全有效的表观遗传畸变中和膳食化合物组合，通过提供较低剂量的这些化合物、增强功效和更高的成本效益，具有预防 BC 的巨大转化潜力。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，拟议的研究将为那些罹患高致命性 ER(-) BC 的高风险且别无选择的女性带来希望。