Combinatorial epigenetic-based prevention of breast cancer

描述（由申请人提供）：常规使用单药饮食方法来预防乳腺癌（BC）可能有局限性，因为这些化合物在单独作用时可能不够有效，无法可靠地预防BC，或者它们可能需要不切实际或不安全的摄入量才能获得显著的疗效。应对这一挑战的一种解决办法是采用组合方法，减少单个天然化合物的剂量，使其组合起来产生更大的功效。我们已经证明，将绿茶多酚（GTPs）和富含萝卜硫素（SFN）的西兰花芽（BSp）组合在人类可食用的安全水平下，对预防自发发展为BC的小鼠BC肿瘤非常有效。我们的研究结果表明，这种gtp和BSp组合膳食方法的有效性取决于这些天然膳食产品显著影响表观遗传基因调控的能力。我们假设gtp和BSp联合使用在中和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的食用这些饮食产品，从而对预防BC产生更大的影响。这些调查很重要，原因有很多。首先，由于对这些膳食产品的联合表观遗传效应知之甚少，阐明这种组合饮食表观遗传方法的影响和机制及其对关键肿瘤相关基因表观遗传学的影响是很重要的。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，以及哪些其他基因可能受到这些化合物的影响。第三，我们还不完全了解这些化合物的组合对不同起源和致癌途径的BC肿瘤的影响。最后，对于雌激素受体阴性[ER(-)] BC的女性来说，选择很少，我们发现gtp和BSp联合治疗在将ER（-）肿瘤转化为ER（+）肿瘤方面非常有效，而ER（+）肿瘤可以很容易地用他莫昔芬（TAM）预防。因此，更充分地了解这些联合方法在预防ER(-) BC中的机制和功效将是重要的。本提案的目标是通过使用我们发明的新技术，如染色质免疫沉淀(ChIP)-基因组亚硫酸酯测序（GBS）或ChIP-GBS和先进的表观基因组技术来应对这些挑战。这项拟议的调查的影响将是显著的，因为全世界有成千上万的妇女受到BC的影响。使用安全有效的表观遗传畸变中和膳食化合物组合，通过提供更低剂量的化合物，增强疗效和更高的成本效益，在预防BC方面具有很高的转化潜力。也有必要鉴定的表观遗传生物标志物

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.