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

描述（由申请人提供）：肥胖是绝经后妇女激素受体（HR）阳性乳腺癌的一个确定的危险因素。这种增加的风险被认为部分是由于脂肪组织产生的雌激素增加，因为脂肪组织是绝经后雌激素合成酶芳香化酶的主要作用部位。鉴于目前肥胖的流行，迫切需要制定基于机制的战略来降低这部分人群的癌症风险。雌激素剥夺是乳腺癌预防和治疗的常用方法，但serm和芳香化酶抑制剂都有明显的副作用，限制了它们在预防中的广泛应用。我们假设，通过靶向驱动芳香化酶表达增加的途径，将有可能抑制脂肪组织（包括乳房）中雌激素的过度产生，从而降低超重和肥胖人群患hr阳性乳腺癌的风险。重要的是，在这方面，环氧化酶（COX）衍生的前列腺素E2 （PGE2）在刺激编码芳香酶的CYP19基因的转录中发挥了关键作用。我们已经报道了COX-2在乳腺（MG）中的过表达导致PGE2产生增加和芳香化酶表达升高。引人注目的是，我们现在已经发现，在肥胖小鼠模型中，MG和内脏脂肪（VF）都发生了显著的炎症、COX-2表达升高和芳香化酶水平升高。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MG和VF炎症变化导致芳香化酶活性升高，从而增加了HR阳性乳腺癌的风险。因此，本提案的目标是评估破坏花生四烯酸代谢的策略，从而抑制PGE2- >芳香化酶轴，最终目标是“正常化”与肥胖相关的芳香化酶水平升高。在SA1中，我们将根据我们在PGE2介导的芳香酶诱导中涉及BRCA1、Sirt-1和CBP/p300的新数据，定义PGE2、BRCA1、组蛋白乙酰化和芳香酶诱导之间的相互关系。在SA2中，我们将利用敲除小鼠品系评估COX- 1、mPGES-1或15-PGDH（参与PGE2合成或分解代谢的酶）是否是MG和VF中芳香酶表达和活性的决定因素。在SA3中，我们将探索n-3脂肪酸调节PGE2- >芳香化酶途径的机制，因为n-3脂肪酸已被证明可以抑制PGE2的合成并预防实验性乳腺癌。最后，在SA4中，我们将测试n-3脂肪酸单独或与COX-2抑制剂联合是否能抑制肥胖小鼠MG和VF体内的炎症和降低芳香酶水平。如果药物或饮食方法能够破坏肥胖->炎症->COX- >芳香化酶途径，这将是一个重大的进步，并加强了解决女性类似问题的基本原理。总的来说，拟议研究的结果将为降低hr阳性乳腺癌风险的策略提供新的见解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We have shown that obesity drives an inflammatory process in adipose tissue leading to increased expression of the estrogen synthesizing enzyme aromatase. Here we propose to test if either a pharmacological or dietary approach, or the combination thereof, disrupts the obesity-->inflammation-->cyclooxygenase-->aromatase pathway. Positive findings in this study would provide a platform for evaluating new strategies for reducing hormone receptor-positive breast cancer.