Targeting the Obesity-Inflammation-COX-Aromatase Axis to Lower Breast Cancer Risk

项目摘要/摘要 肥胖是绝经后激素受体(HR)阳性乳腺癌的既定危险因素 女人。这种风险的增加被认为部分归因于脂肪产生的雌激素增加。 组织，因为脂肪组织是雌激素合成酶芳香酶后的主要作用部位 更年期。鉴于目前肥胖症的流行，迫切需要制定基于机制的 在这部分人口中降低癌症风险的战略。雌激素缺乏是一种常见的 用于乳腺癌预防和治疗的方法，但SERM和芳香酶抑制剂都有 严重的副作用，限制了它们在预防中的广泛使用。我们假设通过将目标对准 促进芳香酶表达增加的途径将有可能抑制雌激素的过度生产 脂肪组织，包括乳房，从而降低超重者患HR阳性乳腺癌的风险 还很胖。在这方面，重要的是已经确定了环氧合酶(COX)衍生的关键作用 前列腺素E_2(PGE_2)在刺激编码芳香酶的CYP19基因转录中的作用。 我们已经报道，COX-2在乳腺(MG)中的过度表达导致PGE2产生增加 和芳香酶表达的升高。令人惊讶的是，我们现在发现显著的炎症，升高 小鼠MG和内脏脂肪(VF)中均存在COX-2表达和芳香化酶水平升高 肥胖症模型。这些令人兴奋的发现提出了一种非常真实的可能性，即肥胖相关的炎症性疾病 MG和VF的变化都有助于芳香酶活性的升高，从而增加了HR- 阳性乳腺癌。因此，这项提案的目标是评估破坏花生四项氏症的策略 酸代谢，从而抑制前列腺素E_2-芳香酶轴，最终目标是“正常化”。 芳香酶水平的升高与肥胖有关。在SA1中，我们将定义相互关系 PGE2、BRCA1、组蛋白乙酰化和芳香酶诱导之间的关系，基于我们新的数据暗示 BRCA1、Sirt-1和CBP/p300在PGE2介导的芳香酶诱导中的作用。在SA2中，我们将评估考克斯是否- 1，mPGES-1或15-PGDH，参与PGE2合成或分解代谢的酶，是PGE2的决定因素 利用基因敲除小鼠品系在MG和VF中表达芳香化酶及其活性。在SA3中，我们将探索 N-3脂肪酸调节前列腺素E_2芳香酶途径的机制(S)，因为n-3脂肪酸有 已被证明能抑制PGE2的合成，并能预防实验性乳腺癌。最后，在SA4中，我们 将测试n-3脂肪酸是否单独或与COX-2抑制剂联合使用，抑制炎症和减少 肥胖小鼠MG和VF体内芳香化酶水平。如果一种药理或饮食方法 扰乱obesity-&gt；inflammation-&gt；COX-&gt；aromatase途径，这将是一个重大的进步 并加强了在女性中解决类似问题的理由。总体而言， 拟议的研究将为降低HR阳性乳腺癌风险的策略提供新的见解。

Project Summary/Abstract Obesity is an established risk factor for hormone receptor (HR)-positive breast cancer in post-menopausal women. This increased risk is thought to be partly attributable to increased estrogen production from adipose tissue, since adipose tissue is the primary site of action of the estrogen-synthesizing enzyme aromatase post climacteric. Given the current epidemic of obesity, there is a pressing need to develop mechanism-based strategies to reduce the cancer risk among this sector of the population. Estrogen deprivation is a commonly used approach for breast cancer prevention and treatment, but both SERMs and aromatase inhibitors have significant side effects that restrict their widespread use for prophylaxis. We hypothesize that by targeting the pathways that drive increased aromatase expression it will be possible to suppress estrogen overproduction in adipose tissues, including the breast, and hence reduce the risk of HR-positive breast cancer in the overweight and obese. Importantly in this respect, a key role has been established for cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) in stimulating transcription of the CYP19 gene which encodes the aromatase enzyme. We have reported that COX-2 overexpression in the mammary gland (MG) leads to increased PGE2 production and elevated aromatase expression. Strikingly, we have now found that significant inflammation, elevated COX-2 expression and increased aromatase levels occur in both the MG and visceral fat (VF) in mouse models of obesity. These exciting findings raise the very real possibility that obesity-related inflammatory changes in both the MG and VF contribute to elevated aromatase activity and thereby an increased risk of HR- positive breast cancer. Therefore, the goal of this proposal is to evaluate strategies for disrupting arachidonic acid metabolism and thereby suppressing the PGE2->aromatase axis, with the ultimate goal of "normalizing" the increased levels of aromatase associated with obesity. In SA1, we will define the interrelationships between PGE2, BRCA1, histone acetylation and aromatase induction, based on our novel data implicating BRCA1, Sirt-1 and CBP/p300 in PGE2-mediated aromatase induction. In SA2, we will evaluate whether COX- 1, mPGES-1 or 15-PGDH, enzymes involved in the synthesis or catabolism of PGE2, are determinants of aromatase expression and activity in the MG and VF using knockout mouse strains. In SA3, we will explore the mechanism(s) by which n-3 fatty acids modulate the PGE2->aromatase pathway, since n-3 fatty acids have been shown to suppress PGE2 synthesis and protect against experimental breast cancer. Finally, in SA4 we will test whether n-3 fatty acids, alone or combined with a COX-2 inhibitor, suppress inflammation and reduce aromatase levels in vivo in the MG and VF of obese mice. If either a pharmacological or dietary approach disrupts the obesity->inflammation->COX->aromatase pathway, this would represent a significant advance and strengthen the rationale for addressing similar questions in women. Collectively, the results of the proposed studies will offer new insights into strategies to reduce the risk of HR-positive breast cancer.