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

项目总结/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 妇女这种增加的风险被认为是部分归因于增加的雌激素生产从脂肪 组织，因为脂肪组织是雌激素合成酶芳香化酶后的主要作用部位。 更年期鉴于目前肥胖的流行，迫切需要开发基于机制的 降低这部分人口癌症风险的战略。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其广泛用于预防。我们假设通过瞄准 驱动芳香酶表达增加的途径，将有可能抑制雌激素的过度产生， 脂肪组织，包括乳房，因此降低了超重者患HR阳性乳腺癌的风险。 肥胖重要的是，在这方面，已经确定了环加氧酶（考克斯）衍生的 前列腺素E2（PGE 2）刺激编码芳香酶的CYP 19基因的转录。 我们已经报道过考克斯-2在乳腺（MG）中的过表达导致PGE 2产生增加 和升高的芳香化酶表达。令人惊讶的是，我们现在已经发现， 考克斯-2的表达和芳香化酶水平的增加发生在MG和内脏脂肪（VF）在小鼠 肥胖的模型。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可能是由肥胖引起的。 MG和VF的变化都有助于芳香化酶活性升高，从而增加HR的风险。 乳腺癌阳性。因此，本提案的目标是评估干扰花生四烯酸的策略， 酸代谢，从而抑制PGE 2->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SA 1中，我们将定义相互关系 PGE 2、BRCA 1、组蛋白乙酰化和芳香化酶诱导之间的关系，基于我们的新数据， BRCA 1、Sirt-1和CBP/p300在PGE 2介导的芳香化酶诱导中的作用在SA 2中，我们将评估考克斯- 1、mPGES-1或15-PGDH，参与PGE 2合成或催化的酶，是PGE 2的决定因素。 使用敲除小鼠品系在MG和VF中的芳香酶表达和活性。在SA 3中，我们将探索 n-3脂肪酸调节PGE 2->芳香酶途径的机制，因为n-3脂肪酸具有 研究表明，它可以抑制PGE 2的合成，预防实验性乳腺癌。最后，在SA 4中， 将测试是否n-3脂肪酸，单独或与考克斯-2抑制剂，抑制炎症和减少 肥胖小鼠的MG和VF中的体内芳香酶水平。如果药物或饮食方法 破坏肥胖->炎症->考克斯->芳香化酶途径，这将代表一个重大进展 并加强解决妇女类似问题的理由。总的来说， 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.