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个体的遗传背景它最初是在人类生命早期产生的；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编程过程，涉及极其精确的时间控制基因激活/沉默表达，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特性的饮食成分被认为对包括乳腺癌在内的癌症预防有影响。生物活性膳食成分，萝卜硫素（SFN），十字花科蔬菜中富含的异硫氰酸盐，如西兰花芽（BSp），大豆制品中的染料木素（GE）是强表观遗传调节剂，在体外和体内似乎可以预防乳腺癌。我们的初步研究表明，母亲饮食中的BSp或GE治疗会影响成年后乳腺癌的发病率。特别是，在C3(1)-SV40标签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饮食促进乳腺癌的发展，自发发展为乳腺癌。这些令人激动的结果表明，表观遗传饮食成分诱导的经胎盘乳腺癌干预可能涉及一个全面的机制，迫切需要母亲的饮食指导，这可能有利于早期乳腺癌的预防。然而，尽管有这些令人鼓舞的结果，我们对SFN/BSp或GE在人类乳腺癌早期化学预防中的表观遗传机制的了解仍有许多空白。假设：我们的主要假设是BSp或转基因生物活性天然植物产品通过影响表观遗传谱影响早期胚胎发育，从而导致转基因小鼠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影响；2)评估特定的表观遗传控制关键基因，如hTERT；研究ER¿和p16INK4a对母亲膳食BSp或GE治疗的响应，以及3)评估母亲膳食BSp或GE对表观基因组谱的影响，包括甲基组和乙酰组改变，以及确定该方案控制早期乳腺癌化学预防的候选表观遗传基因。拟开展研究的目的和意义：本拟开展研究的目的是确定母体BSp或GE饮食对早期乳腺癌干预的有效性及其潜在的表观遗传机制。本研究可能通过产前和/或产后膳食补充剂的适当管理导致早期乳腺癌预防的转化乳腺癌化学预防潜力。乳腺癌影响着全世界成千上万的妇女，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.