Combinatorial epigenetic-based prevention of breast cancer

描述(申请人提供)：预防乳腺癌(BC)的单剂饮食方法的传统使用可能有局限性，因为当这些化合物单独作用以可靠地预防BC时，这些化合物可能不够有效，或者它们可能需要不切实际或不安全的消费水平才能获得显著效果。这一挑战的一个解决方案是组合方法，允许减少单独的天然化合物的剂量，这些化合物组合在一起可以产生更大的功效。我们已经证明，结合绿茶多酚(GTP)和萝卜硫素(SFN)富含西兰花芽(BSP)在人类食用的安全水平上可以非常有效地预防自发发展为BC的小鼠的BC肿瘤。我们的结果表明，GTP和BSP的这种组合饮食方法的有效性取决于这些天然饮食产品显著影响表观遗传基因调控的能力。我们假设联合GTP和BSP在中和BC中关键肿瘤相关基因的表观遗传异常以及表观基因组改变方面是非常有效的，并且这种组合饮食方法允许更少的这些饮食产品的消费，从而在预防BC方面产生更大的影响。这些调查之所以重要，原因有很多。首先，由于人们对这些饮食产品的联合表观遗传效应知之甚少，因此有必要阐明这种联合饮食表观遗传学方法的影响和机制，以及它对关键肿瘤相关基因表观遗传学的影响。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，我们还不完全了解这些化合物的组合会对不同来源和致癌途径的BC肿瘤产生什么影响。最后，对于患有雌激素受体阴性[ER(-)]BC的女性来说，几乎没有选择，我们发现联合GTPS和BSP在将ER(-)肿瘤转化为ER()肿瘤方面非常有效，而三苯氧胺可以很容易地预防()。因此，更充分地了解这些组合方法在预防ER(-)BC方面的机制和有效性将是重要的。这项提议的一个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)-基因组亚硫酸盐测序(GBS)或CHIP-GBS以及先进的表观基因组学技术。这项拟议的调查的影响将是重大的，因为全世界数十万妇女受到BC的影响。使用安全有效的表观遗传变异中和饮食化合物组合，通过提供较低剂量的这些化合物、提高疗效和更大的成本效益，具有很高的预防BC的翻译潜力。还需要鉴定表观遗传生物标记物 这将有助于BC的易感、诊断和预后。最后，拟议的研究将为那些患有高度致命的ER(-)BC的高风险和几乎没有选择的妇女带来希望。

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.