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.

预防高度致命的雌激素受体阴性 [ER(-)] 乳腺癌的组合饮食方法 (BC) 比单药方法具有许多优势，最显着的是具有更高功效的潜力 不会增加毒性风险。我们已经证明，组合绿茶多酚可以抑制 DNA 西兰花芽中的甲基转移酶和萝卜硫素可显着抑制组蛋白脱乙酰酶 延迟 ER(-) BC 的发生并在实用且安全的饮食水平下阻止其进展。我们的成果也 研究表明表观遗传机制对于 ER(-) BC 预防的功效具有重要的机制作用 通过这些饮食。母亲或父亲食用这种组合方案可能会导致潜伏期增加 并减少了食用对照饮食的 ER(-) BC 后代的肿瘤生长。我们的实地驱动研究 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 强烈支持跨代表观遗传效应。我们的假设是组合绿茶 多酚和富含萝卜硫素的西兰花芽饮食可以延长其表观遗传中和 ER(-) BC 通过胎盘效应或通过 跨代效应。这些研究对于解决代际效率问题非常重要 组合癌症预防以及介导这种效应的表观遗传机制。自从 我们的初步研究结果表明，食用这种组合饮食可以通过 父系和母系血统都可以预防对照喂养的雌性后代中的 ER(-) BC，这强烈表明 我们发现的配子发生表观遗传变化对于 对于喂食这种组合饮食的母亲来说，除了跨胎盘效应之外，还存在跨代效应。这 通过这种组合表观遗传调节对关键肿瘤相关基因的表观遗传控制的父系效应 饮食将极大地有助于阐明这种饮食赋予预防性作用的机制。 对 ER(-) BC 的影响。这项拟议的创新调查的目标之一是解决代际问题 ER(-) 组合表观遗传调节绿茶多酚和 BC 癌症的预防作用 富含萝卜硫素的西兰花芽及其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，因为综合消费 母亲或父亲通过表观遗传调节饮食来延迟和减少后代的 ER(-) BC 对癌症预防的新观点具有广泛的影响。此外，ER(-) BC 常常不同意 癌症治疗的传统模式显着增加了促进其治疗的手段的重要性 预防。通过母亲和/或父亲降低 ER(-) BC 风险的新方法 食用这种组合饮食将大大有助于加强 ER(-) BC 预防 也许还有全世界其他癌症的预防控制。