Combinatorial epigenetic-based prevention of breast cancer

描述（由申请人提供）：预防乳腺癌（BC）的单一药物饮食方法的常规使用可能具有局限性，因为这些化合物在单独作用时可能不足以有效可靠地预防BC，或者它们可能需要不切实际或不安全的食用水平才能获得显著的功效。这一挑战的解决方案是组合方法，其允许减少单个天然化合物的剂量，这些化合物在组合中产生更大的功效。我们已经证明，以人类可食用的安全水平施用的组合的绿色茶多酚（GTP）和富含萝卜硫素（SFN）的西兰花芽（BSp）在预防自发发展BC的小鼠中的BC肿瘤方面是高度有效的。我们的研究结果表明，GTP和BSP的这种组合膳食方法的功效取决于这些天然膳食产品显着影响表观遗传基因调控的能力。我们假设，GTP和BSp组合在中和BC中关键肿瘤相关基因的表观遗传畸变以及表观基因组改变方面非常有效，并且这种组合饮食方法允许更少地消耗这些饮食产品，以在预防BC中产生更大的影响。这些调查之所以重要，有若干原因。首先，重要的是要阐明这种组合饮食表观遗传方法的影响和机制，以及它对关键肿瘤相关基因的表观遗传学的影响，因为对这些饮食产品的组合表观遗传学影响知之甚少。其次，这也很重要，因为我们还不知道这些化合物的表观遗传效应的全球概况，以及这些化合物可能影响哪些其他基因。第三，我们还没有完全了解这些化合物的组合对不同起源和致癌途径的BC肿瘤会产生什么影响。最后，对于雌激素受体阴性[ER（-）] BC的女性，几乎没有选择，我们发现GTP和BSP联合治疗可有效地将ER（-）肿瘤转化为ER（+）肿瘤，这可以通过他莫昔芬（TAM）很容易地预防。因此，更全面地了解这些组合方法在预防ER（-）BC中的机制和功效将是重要的。该提案的目标是通过使用我们发明的新技术来应对这些挑战，例如染色质免疫沉淀（ChIP）-基因组亚硫酸氢盐测序（GBS）或ChIP-GBS和先进的表观基因组技术。这项拟议调查的影响将是重大的，因为全世界有数十万妇女受到BC的影响。表观遗传异常中和膳食化合物的安全有效组合的使用通过提供较低剂量的这些化合物、增强的功效和更大的成本效益而具有预防BC的高转化潜力。还需要鉴定表观遗传生物标志物， 有助于BC的易感性、诊断和预后。最后，这项拟议的研究将为那些处于发展高致命性ER（-）BC高风险和几乎没有选择的女性提供希望。

DESCRIPTION (provided by applicant): The conventional use of single-agent dietary approaches to prevent breast cancer (BC) can have limitations in that these compounds may not be sufficiently efficacious when acting alone to reliably prevent BC or they may require impractical or unsafe levels of consumption to acquire significant efficacy. A solution to this challenge is combinatorial approaches allowing reduced doses of the individual natural compounds that, in combination, render greater efficacy. We have shown that combined green tea polyphenols (GTPs) and sulforaphane (SFN)-enriched broccoli sprouts (BSp) administered at safe levels consumable by humans are highly effective in preventing BC tumors in mice that spontaneously develop BC. Our results indicate that the efficacy of this combinatorial dietary approach of GTPs and BSp depends on the ability of these natural dietary products to significantly impact epigenetic gene regulation. We hypothesize that combined GTPs and BSp are highly effective in neutralizing epigenetic aberrations of key tumor-related genes in BC as well as epigenomic alterations and that this combinatorial dietary approach allows less consumption of these dietary products to render a greater impact in preventing BC. These investigations are important for a number of reasons. First, it is important to elucidate the impac and mechanisms of this combinatorial dietary epigenetic approach and its effects on the epigenetics of key tumor-related genes since little is known about the combined epigenetic effects of these dietary products. Second, it is also important because we do not yet know the global profile of the epigenetic effects of these compounds and what other genes may be impacted by these compounds. Third, we do not yet fully understand what impact the combination of these compounds will have on BC tumors of different origins and pathways of carcinogenesis. Finally, there are few options for women who develop estrogen receptor-negative [ER(-)] BC and we have found that combined GTPs and BSp is highly effective in converting ER(-) tumors to ER(+) tumors that can be readily prevented with tamoxifen (TAM). It will therefore be important to more fully understand the mechanisms and efficacy of these combinatorial approaches in preventing ER(-) BC. A goal of this proposal is to confront these challenges through the use of novel techniques we have invented such as chromatin immunoprecipitation (ChIP)-genomic bisulfite sequencing (GBS) or ChIP-GBS and advanced epigenomic technologies. The impact of this proposed investigation will be significant since hundreds of thousands of women worldwide are affected by BC. The use of safe and effective combinations of epigenetic aberration-neutralizing dietary compounds has high translational potential for preventing BC by providing lower doses of these compounds, enhanced efficacy and greater cost effectiveness. There is also a need for identification of epigenetic biomarkers of BC that will aid in the predisposition, diagnosis and prognosis of BC. Finally, the proposed study will provide hope for women who are at high risk of developing highly lethal ER(-) BC and who have few options.