Maternal epigenetic dietary effects on early breast cancer prevention

背景：乳腺癌是美国最常见的癌症，也是女性癌症死亡的第二大原因。乳腺癌最重要的风险因素之一是最初在人类生命早期产生的个体遗传背景;例如，在胚胎发生和胎儿在子宫内发育的过程中。早期胚胎发生包括一系列涉及极其精确的时间控制的基因激活/沉默表达的编程过程，并且表观遗传控制被认为在调节早期胚胎发育中起关键作用。具有影响表观遗传过程的特性的膳食成分被认为对预防癌症（包括乳腺癌）具有作用。具有生物活性的膳食成分，萝卜硫素（SFN），一种富含十字花科蔬菜如花椰菜芽（BSp）的异硫氰酸酯，以及大豆产品中的染料木素（GE）是强大的表观遗传调节剂，似乎可以在体外和体内预防乳腺癌。我们的初步研究表明，母亲的饮食BSP或GE治疗影响成年后的乳腺癌发病率。特别是，在自发发展乳腺癌的C3（1）-SV40 Tag转基因小鼠的后代中，母体BSp饮食导致乳腺癌发病延迟，而GE饮食促进乳腺癌发展。这些挑衅性的结果表明，一个全面的机制可能涉及表观遗传饮食成分诱导的经胎盘乳腺癌干预和母亲的饮食指导是迫切需要的，可能有利于早期乳腺癌的预防。尽管这些有希望的结果，但是，在我们的知识SFN/BSp或GE在人类乳腺癌的早期化学预防的表观遗传机制有很多差距。假设：我们的主要假设是，BSp或GE生物活性天然植物产品通过影响表观遗传特征影响早期胚胎发育，从而导致转基因小鼠模型在生命后期对乳腺癌的不同易感性。具体目标：因此，本提案的具体目的是：1）确定早期BSp或GE给药对转基因小鼠模型后代自发性乳腺癌发展的时间效应，2）评估特定的表观遗传学控制的关键基因，如hTERT、ER？和p16INK4a对母体膳食BSp或GE处理的响应，以及3）评估母体BSp或GE饮食对表观基因组谱的影响，包括甲基化组和乙酰基组改变，以及确定通过该方案控制早期乳腺癌化学预防的候选表观遗传基因。拟议研究的目的和意义：本提案的目的是确定母体BSp或GE饮食对早期乳腺癌干预的有效性以及潜在的表观遗传机制。这项研究可能会导致翻译乳腺癌化学预防的潜力，通过适当的管理产前和/或产后的膳食补充剂，导致早期乳腺癌的预防。乳腺癌影响着全世界数十万妇女，阐明通过天然生物活性产品预防乳腺癌将产生全球影响。

DESCRIPTION (provided by applicant): Background: Breast cancer is the most common cancer in the United States and the second leading cause of cancer death in women. One of the most important risk factors for breast cancer is the individual genetic background which is initially generated early in human life; for example, during the processes of embryogenesis and fetal development in utero. Early embryogenesis includes a series of programming processes involving extremely accurate time-controlled gene activation/silencing expression, and epigenetic control is believed to play a key role in regulating early embryonic development. Dietary components with properties in influencing epigenetic processes are believed to have effects on cancer prevention including breast cancer. The bioactive dietary components, sulforaphane (SFN), an isothiocyanate enriched in cruciferous vegetables such as broccoli sprouts (BSp), and genistein (GE) in soybean products are strong epigenetic modulators that appear to lead to prevention of breast cancer in vitro and in vivo. Our preliminary studies have shown that maternal dietary BSp or GE treatment impact breast cancer incidence later in adult life. In particular, the maternal BSp diet results in a delay of breast cancer onset, whereas a GE diet promotes breast cancer development, in the offspring of C3(1)-SV40 Tag transgenic mice that spontaneously develop breast cancer. These provocative results suggest a comprehensive mechanism may be involved in epigenetic dietary components-induced transplacental breast cancer intervention and maternal diet instruction is urgently needed that may benefit early breast cancer prevention. Despite these promising results, however, there are many gaps in our knowledge of the epigenetic mechanisms of SFN/BSp or GE in early chemoprevention of human breast cancer. Hypothesis: Our main hypothesis is that BSp or GE bioactive natural plant products impact early embryonic development by affecting epigenetic profiles resulting in different susceptibility to breast cancer later in life in the transgenic mouse models. Specific Aims: The specific aims of this proposal are therefore to 1) determine the temporal effects of early BSp or GE administration on spontaneous breast cancer development in the offspring of transgenic mouse models, 2) evaluate specific epigenetic-controlled key genes such as hTERT, ER¿ and p16INK4a in response to maternal dietary BSp or GE treatment and 3) assess the impact of maternal BSp or GE diet on epigenomic profiles including methylome and acetylome alterations as well as determination of candidate epigenetic genes in control of early breast cancer chemoprevention by this regimen. Goal and Significance of the Proposed Research: The goal of this proposal is to determine the effectiveness of maternal BSp or GE diet on early life breast cancer intervention and the potential epigenetic mechanisms. This study may lead to translational breast cancer chemopreventive potential by appropriate administration of prenatal and/or postnatal dietary supplements leading to early breast cancer prevention. Breast cancer affects hundreds of thousands of women world-wide and elucidation of its prevention through natural bioactive products will have global impact.