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: 10078944
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078944
• 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; Prognosis; Property; Recommendation; Regimen; Regulation; Risk; Sulforaphane; Techniques; Technology; Telomerase; Tissues; Transgenic Mice; Vegetables; Woman; advanced disease; bisulfite sequencing; breast cancer progression; cancer prevention; cancer risk; cancer therapy; chromatin immunoprecipitation; combinatorial; cruciferous vegetable; dietary; dietary approach; epidemiology study; epigenetic marker; epigenomics; innovation; malignant breast neoplasm; model design; mortality; mouse model; novel; offspring; prevent; public health relevance

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.

通过阐明膳食植物对健康的影响，可以大大增强其在维持健康方面的应用 表观遗传机制、其综合影响及其在不同生命阶段（尤其是生命早期）的功效。 表观遗传畸变通常会改变关键基因表达，这些基因表达对于维持健康和延缓衰老至关重要。 控制癌症的发生并减少其影响。然而，人们对饮食的影响知之甚少。 生命早期组合食用植物药对表观遗传机制和患癌症风险的影响。 我们的研究表明，富含绿茶多酚 (GTP) 和萝卜硫素 (SFN) 的西兰花芽 (BSp)，以人类可食用的安全水平联合给药，可以非常有效地增加 自发发展为雌激素受体 (ER) 阴性 [ER(-)] 乳腺癌的小鼠的癌症潜伏期 在生命早期实施这可能会更有效。重要的是，尽管大多数 ER(+) 乳房 癌症一旦形成，对治疗的反应相对较高，如果 ER(-) 乳腺癌在以下情况下死亡率很高： 不被阻止发展。因此，减少 ER(-) 乳腺癌的癌症预防方法 迄今为止，这对癌症死亡率的影响最大。我们的结果表明，功效 这种饮食方法的效果取决于这些植物成分显着影响表观遗传基因的能力 规定。我们的假设是，生命早期食用 GTP 和 BSp 组合对于以下方面非常有效： 中和导致 ER(-) BC 形成的关键基因的表观基因组改变和表观遗传控制， 进展。这些研究对于确定植物药在生命各个阶段的功效非常重要，因此 他们的消费将优化癌症预防的潜力。我们还没有完全理解 这些植物在生命的不同阶段消耗的表观遗传机制，特别是组合使用 因为它们经常被消耗。此外，这些植物对全球表观基因组过程的影响 各个年龄尚不清楚。这项拟议调查的主要目标是面对这些持续存在的问题 挑战。将这些植物成分纳入年轻人的饮食中是安全的，并且可能会产生重要的影响 修改饮食方案以增加癌症潜伏期并显着降低 ER(-) 的发病率 乳腺癌死亡人数。染色质免疫沉淀-基因组亚硫酸氢盐测序等新技术 将采用我们发明的（ChIP-GBS）以及多种先进的表观基因组技术。 阐明癌症潜伏期的表观遗传机制并降低患癌症的风险将导致 全世界数十万人的健康状况显着改善。这项调查将 也为鉴定不同阶段乳腺癌表观遗传生物标志物提供重要信息 生活的一部分，这将有助于阐明乳腺癌的易感性、诊断和预后。最多 重要的是，在生命早期使用安全有效的表观遗传畸变中和植物药物具有很高的效果。 增加潜伏期并减少 ER(-) 乳腺癌影响的转化潜力。

项目成果

DNA methylation methods: Global DNA methylation and methylomic analyses.

• DOI: 10.1016/j.ymeth.2020.10.002
• 发表时间: 2021-03
• 期刊: Methods (San Diego, Calif.)
• 作者: Li S;Tollefsbol TO
• 通讯作者: Tollefsbol TO

Epigenetic biomarkers: Current strategies and future challenges for their use in the clinical laboratory.

• DOI: 10.1080/10408363.2017.1410520
• 发表时间: 2017-11
• 期刊: Critical reviews in clinical laboratory sciences
• 影响因子: 10
• 作者: García-Giménez JL;Seco-Cervera M;Tollefsbol TO;Romá-Mateo C;Peiró-Chova L;Lapunzina P;Pallardó FV
• 通讯作者: Pallardó FV

Association of high-sensitivity C-reactive protein and odds of breast cancer by molecular subtype: analysis of the MEND study.

• DOI: 10.18632/oncotarget.27991
• 发表时间: 2021-06-22
• 期刊: Oncotarget
• 作者: Gupta A;Oyekunle T;Salako O;Daramola A;Alatise O;Ogun G;Adeniyi A;Deveaux A;Saraiya V;Hall A;Ayandipo O;Olajide T;Olasehinde O;Arowolo O;Adisa A;Afuwape O;Olusanya A;Adegoke A;Tollefsbol TO;Arnett D;Muehlbauer MJ;Newgard CB;H3 Africa Kidney Research Network;Akinyemiju T
• 通讯作者: Akinyemiju T

Association of Life-Course Educational Attainment and Breast Cancer Grade in the MEND Study.

MEND 研究中生命历程教育程度与乳腺癌等级的关联。

• DOI: 10.5334/aogh.3142
• 发表时间: 2021
• 期刊: Annals of global health
• 影响因子: 2.9
• 作者: Gupta A;Jones K;Deveaux A;Bevel M;Salako O;Daramola A;Hall A;Alatise O;Ogun G;Adeniyi A;Ojo A;Ayandipo O;Olajide T;Olasehinde O;Arowolo O;Adisa A;Afuwape O;Olusanya A;Adegoke A;Tollefsbol TO;Arnett D;Newgard CB;Akinyemiju T
• 通讯作者: Akinyemiju T

The Role of Non-Coding RNAs and Isothiocyanates in Cancer.

• DOI: 10.1002/mnfr.201700913
• 发表时间: 2018-09
• 期刊: Molecular nutrition & food research
• 影响因子: 5.2
• 作者: Martin SL;Royston KJ;Tollefsbol TO
• 通讯作者: Tollefsbol TO