Early life prevention of breast cancer with combined epigenetic botanicals

结合表观遗传植物药物在生命早期预防乳腺癌

• 批准号: 9237094
• 负责人: TRYGVE O TOLLEFSBOL
• 金额: $ 33.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237094
• 关键词: Address; Affect; Age; Botanicals; Breast Cancer Prevention; Broccoli - dietary; Cabbage - dietary; Cancer Etiology; Cauliflower; Clinical Trials; Consumption; Diagnosis; Diet; Disease; Epigallocatechin Gallate; Epigenetic Process; Estrogen Receptors; Estrogen receptor negative; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; Genomics; Goals; Green tea; Growth; Health; Human; Incidence; Individual; Investigation; Isothiocyanates; Kale - dietary; Laboratories; Lead; Life; Malignant Neoplasms; Mammary Neoplasms; Morbidity - disease rate; Mus; Nature; Pathogenesis; Pathologic; Pathology; Predisposition; Prevention approach; Preventive; Process; Property; Recommendation; Regimen; Regulation; Risk; Sulforaphane; Techniques; Technology; Telomerase; Tissues; Transgenic Mice; Vegetables; Woman; advanced disease; bisulfite sequencing; cancer prevention; cancer risk; cancer therapy; chromatin immunoprecipitation; combinatorial; cruciferous vegetable; dietary approach; epidemiology study; epigenetic marker; epigenomics; innovation; malignant breast neoplasm; model design; mortality; mouse model; novel; offspring; outcome forecast; prevent; public health relevance; tumor progression

Use of dietary botanicals for maintaining health can be greatly enhanced through elucidation of their effects on epigenetic mechanisms, their combined impact and their efficacy at different life stages, especially early in life. Epigenetic aberrations often alter key gene expressions that are crucial in maintaining health and delaying the onset and reducing the impact of cancer. However, very little is known with respect to the impact of dietary botanicals consumed in combination early in life on epigenetic mechanisms and the risk of developing cancer. Our studies have indicated that green tea polyphenols (GTPs) and sulforaphane (SFN)-rich broccoli sprouts (BSp), administered in combination at safe levels consumable by humans, are highly effective in increasing cancer latency in mice that spontaneously develop estrogen receptor (ER)-negative [ER(-)] breast cancer and that this may be more effective when administered early in life. It is important that although most ER(+) breast cancer is relatively highly responsive to therapy once it forms, ER(-) breast cancer has high mortality rates if it is not prevented from developing. Therefore, cancer prevention approaches that reduce ER(-) breast cancer will have by far the greatest impact on the incidence of cancer fatalities. Our results indicate that the efficacy of this dietary approach depends on the ability of these botanicals to significantly impact epigenetic gene regulation. Our hypothesis is that early life consumption of combined GTPs and BSp is highly effective in neutralizing epigenomic alterations and epigenetic control of key genes that lead to ER(-) BC formation and progression. These studies will be important to determine the efficacy of botanicals at various stages of life so that their consumption will optimize the potential for cancer prevention. We do not yet fully understand the epigenetic mechanisms of these botanicals consumed at different stages of life and especially in combination as they are often consumed. Further, the impact of these botanicals on global epigenomic processes at various ages is not yet known. A major goal of this proposed investigation is to confront these persistent challenges. The incorporation of these botanicals into diets of the young is safe and could lead to important revisions of dietary regimens to increase cancer latency and to significantly reduce the incidence of ER(-) breast cancer fatalities. Novel techniques such as chromatin immunoprecipitation-genomic bisulfite sequencing (ChIP-GBS) that we invented as well as several advanced epigenomic technologies will be employed. Elucidation of the epigenetic mechanisms for cancer latency and reducing the risk of cancer will result in significant increases in the health of hundreds of thousands of individuals worldwide. This investigation will also provide essential information for identification of epigenetic biomarkers of breast cancer at different stages of life that will facilitate elucidation of the predisposition, diagnosis and prognosis of breast cancer. Most importantly, the use of safe and effective epigenetic aberration-neutralizing botanicals in early life has high translational potential for increasing the latency and reducing the impact of ER(-) breast cancer.

通过阐明其对饮食植物学的影响，可以大大增强饮食植物学对健康的影响 表观遗传机制，它们在不同生活阶段，尤其是生命早期的综合影响和功效。 表观遗传畸变通常会改变关键基因表达，这对于维持健康至关重要 发作和减少癌症的影响。但是，关于饮食的影响很少 生命早期就表观遗传机制和患癌症的风险结合起来消耗的植物药。 我们的研究表明，绿茶多酚（GTPS）和硫烷（SFN）-Rich Broccoli芽 （BSP），以人类消耗的安全水平组合管理，在增加 自发发展雌激素受体（ER）阴性[ER（ - ）]乳腺癌和 在生命早期管理时，这可能会更有效。重要的是，尽管大多数ER（+）乳房 癌症对治疗的反应相对较高，一旦形成，ER（ - ）乳腺癌的死亡率很高。 不能阻止发展。因此，预防癌症的方法可以减少ER（ - ）乳腺癌 到目前为止，将对癌症死亡的发病率产生最大的影响。我们的结果表明功效 这种饮食方法取决于这些植物学物质显着影响表观遗传基因的能力 规定。我们的假设是，联合GTP和BSP的早期寿命在 对关键基因的中和表观基因组改变和表观遗传控制，导致ER（ - ）BC形成和 进展。这些研究对于确定植物在生活的各个阶段的疗效非常重要，因此 他们的消费将优化预防癌症的潜力。我们还不完全了解 这些植物体的表观遗传机制在生活的不同阶段，尤其是组合消耗 因为它们经常被消耗。此外，这些植物体对全球表观基因组过程的影响 各种年龄尚不清楚。这项拟议调查的主要目标是面对这些持久性 挑战。将这些植物药掺入年轻的饮食中是安全的，可能会导致重要 修订饮食方案以增加癌症潜伏期，并显着降低ER的发生率（ - ） 乳腺癌死亡。新型技术，例如染色质免疫沉淀基因组硫酸盐测序 （CHIP-GB）我们发明的以及将采用几种高级表观基因组技术。 阐明癌症潜伏期的表观遗传机制并降低癌症的风险将导致 全球成千上万个人的健康状况大大提高。这项调查会 还提供基本信息，以鉴定不同阶段的乳腺癌表观遗传生物标志物 生活将有助于阐明乳腺癌的易感性，诊断和预后。最多 重要的是，在早期使用安全有效的表观遗传畸变 - 中和植物的使用很高 翻译潜力增加潜伏期并减少ER（ - ）乳腺癌的影响。