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.

预防高致命性雌激素受体阴性[ER（-）]乳腺癌的组合饮食方法 (BC)与单药疗法相比， 而不会增加毒性风险。我们已经证明，结合绿色茶多酚，抑制DNA 西兰花芽中的甲基转移酶和萝卜硫素抑制组蛋白去乙酰化酶， 在实际和安全的饮食水平上延迟ER（-）BC启动并阻止其进展。我们的研究结果也 表明表观遗传机制对ER（-）BC预防的功效是重要的 通过这些饮食。母亲或父亲食用这种组合方案可导致潜伏期增加 并且在食用对照饮食的ER（-）BC后代中减少肿瘤生长。我们的实地驾驶研究 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 强烈支持跨代表观遗传效应。我们的假设是组合绿色茶 富含多酚和萝卜硫素的西兰花芽饮食可以延长其表观遗传中和ER（-）BC 通过经胎盘作用或通过 跨代效应。这些研究对于解决生育效能问题具有重要意义。 组合癌症预防和介导这种效应的表观遗传机制。以来 我们的初步研究结果表明，这种组合饮食的消费可以通过 父亲以及母亲的血统，以防止ER（-）BC在控制喂养的女性后代，这强烈表明， 我们所发现的配子发生的表观遗传变化对于 在喂养这种组合饮食的母亲中，除了经胎盘效应外，还存在跨代效应。的 通过这种组合的表观遗传调节， 饮食将大大有助于阐明这种饮食赋予预防作用的机制， 对ER（-）BC的影响。这一创新研究的目标之一是解决代际问题。 组合表观遗传学调节绿色茶多酚和 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，因为消费量的总和 通过母亲或父亲的表观遗传调节饮食来延迟和减少其后代的ER（-）BC， 对癌症预防的新前景有着广泛的影响。此外，ER（-）BC通常与 传统的癌症治疗模式，这显著增加了促进其治疗的手段的重要性。 预防通过母体和/或父体途径降低ER（-）BC风险的新方法 这种组合饮食的消费将大大有助于增强ER（-）BC预防 也许还能预防世界范围内的其他癌症。