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: 10542804
• 负责人: TRYGVE O TOLLEFSBOL
• 金额: $ 33.73万
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542804
• 关键词: Affect; Automobile Driving; Breast Cancer Prevention; Breast Cancer Risk Factor; Broccoli - dietary; Chemoprevention; Conceptions; Consumption; DNA Modification Methylases; DNA methyltransferase inhibition; Data; Diet; Disease; Epigallocatechin Gallate; Epigenetic Process; Estrogen decline; Estrogen receptor negative; Fathers; Female; Fetus; Gene Expression; Generations; Genes; Germ Cells; Goals; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Investigation; Life; Malignant Neoplasms; Mediating; Mothers; Mus; Parents; Prevention; Preventive; Process; Regimen; Risk; Risk Reduction; Severities; Solid; Statistical Data Interpretation; Sulforaphane; Time; Toxic effect; Tumor Suppression; Woman; cancer initiation; cancer prevention; cancer therapy; combinatorial; dietary; dietary approach; dietary control; efficacious treatment; epigenome; epigenomics; innovation; malignant breast neoplasm; novel; novel strategies; offspring; prevent; promoter; public health relevance; success; transgenerational epigenetic inheritance; translational potential; tumor; tumor growth

Combinatorial dietary approaches to prevent highly fatal estrogen receptor-negative [ER(-)] breast cancer (BC) can offer many advantages over single-agent approaches, most notably the potential for greater efficacy without increased risk of toxicity. We have shown that combined green tea polyphenols that inhibit DNA methyltransferases and sulforaphane in broccoli sprouts that inhibits histone deacetylases can significantly delay ER(-) BC initiation and impede its progression at practical and safe dietary levels. Our results have also shown that the epigenetic machinery is mechanistically important to the efficacy of ER(-) BC prevention by these diets. Maternal or paternal consumption of this combinatorial regimen can lead to increased latency and reduced tumor growth in ER(-) BC offspring that have consumed a control diet. Our field-driving studies show for the first time that this combinatorial diet impacts the epigenome and gene expression of gametes strongly supporting transgenerational epigenetic effects. Our hypothesis is that combinatorial green tea polyphenols and sulforaphane-enriched broccoli sprout diets can extend their epigenetic-neutralizing ER(-) BC preventive effects from one generation to another either through transplacental effects or through transgenerational effects. These studies will be important to resolving the generational efficacy of combinatorial cancer prevention and the epigenetic mechanisms through which this effect is mediated. Since our preliminary findings have indicated that consumption of this combinatorial diet can operate through the paternal as well as maternal lineage to prevent ER(-) BC in control-fed female offspring, this strongly suggests that the gametogenic epigenetic changes we have discovered have mechanistic importance for transgenerational effects in addition to transplacental effects in mothers fed this combinatorial diet. The paternal effects on epigenetic control of key tumor-related genes by this combinatorial epigenetic-modulating diet will contribute significantly to elucidation of the mechanisms through which this diet confers preventive effects on ER(-) BC. One of the goals of this proposed innovative investigation is to resolve the generational ER(-) BC cancer preventive impact of combinatorial epigenetic-modulating green tea polyphenols and sulforaphane-enriched broccoli sprouts and the epigenetic and epigenomic mechanisms responsible for their efficacy. This proposed investigation will have considerable impact in that the consumption of a combined epigenetic-modulating diet by either the mother or father to delay and reduce ER(-) BC in their offspring would have broad implications for new perspectives for cancer prevention. Further, ER(-) BC is often recalcitrant to conventional modes of cancer therapy which significantly increases the importance of means to facilitate its prevention. Novel approaches to reducing the risk of ER(-) BC through maternal and/or paternal consumption of this combinatorial diet would contribute significantly to enhanced ER(-) BC prevention and perhaps preventive control of other cancers worldwide.

组合饮食方法可预防高致命的雌激素受体阴性[ER（ - ）]乳腺癌 （bc）比单机构方法可以提供许多优势，最值得注意的是提高功效的潜力 没有增加毒性的风险。我们已经表明，抑制DNA的绿茶多酚的组合 西兰花新芽中的甲基转移酶和硫烷，抑制组蛋白脱乙酰基酶的甲基转移酶可以显着 延迟ER（ - ）BC的启动，并阻碍其在实际饮食水平上的进展。我们的结果也有 表明表观遗传机械在机理上对ER（ - ）预防的功效很重要 通过这些饮食。该组合方案的母亲或父亲的消费会导致潜伏期增加 并减少了消耗对照饮食的ER（ - ）BC后代的肿瘤生长。我们的现场驾驶研究 首次表明这种组合饮食会影响配子的表观基因组和基因表达 强烈支持转世表观遗传效应。我们的假设是组合绿茶 多酚和富含硫烷的西兰花发芽饮食可以延长其表观遗传中和中和ER（ - ）BC 通过移植效应或通过 转世效应。这些研究对于解决世代疗效至关重要 组合癌的预防和这种作用介导的表观遗传机制。自从 我们的初步发现表明，这种组合饮食的消费可以通过 父亲和母体谱系，以防止对照喂养的女性后代的ER（ - ）BC，这强烈建议 我们发现的配配物的表观遗传变化对 除了喂养这种联合饮食的母亲的移植作用外，跨代作用。这 该联合表观遗传调节对关键肿瘤相关基因表观遗传控制的父亲对遗传控制的影响 饮食将有助于阐明这种饮食赋予预防性的机制 对ER（ - ）BC的影响。这项拟议的创新调查的目标之一是解决世代相传 ER（ - ）BC癌症的预防性影响绿茶多酚和 富含磺胺的西兰花新芽以及负责其的表观遗传和表观基因组机制 功效。这项拟议的调查将产生相当大的影响，因为 母亲或父亲的表观遗传调节饮食延迟并减少er（ - ）BC的后代 对预防癌症的新观点具有广泛的影响。此外，ER（ - ）BC通常是顽固的 常规的癌症疗法模式，这显着提高了促进其疗法的重要性 预防。通过母体和/或父亲降低ER（ - ）BC风险的新颖方法 这种组合饮食的消费将对增强的ER（ - ）预防产生重大贡献 也许可以预防全球其他癌症。