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

描述（由申请人提供）：肥胖是绝经后女性激素受体（HR）阳性乳腺癌的一个既定风险因素。这种增加的风险被认为部分归因于脂肪组织中雌激素产生的增加，因为脂肪组织是更年期后雌激素合成酶芳香酶的主要作用部位。鉴于目前肥胖症的流行，迫切需要制定基于机制的战略，以降低这部分人口的癌症风险。雌激素剥夺是乳腺癌预防和治疗的常用方法，但SERM和芳香酶抑制剂都有显着的副作用，限制了它们在预防方面的广泛使用。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（包括乳腺）中雌激素的过度产生，从而降低超重和肥胖者患HR阳性乳腺癌的风险。在这方面重要的是，已经确定了环加氧酶（考克斯）衍生的前列腺素E2（PGE 2）在刺激编码芳香酶的CYP 19基因的转录中的关键作用。我们已经报道了考克斯-2在乳腺（MG）中的过表达导致PGE 2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，在肥胖小鼠模型的MG和内脏脂肪（VF）中均发生显著的炎症、升高的考克斯-2表达和增加的芳香化酶水平。这些令人兴奋的发现提出了非常真实的可能性，即MG和VF中与肥胖相关的炎症变化有助于芳香酶活性升高，从而增加HR阳性乳腺癌的风险。因此，本提案的目标是评估用于破坏花生四烯酸代谢并由此抑制PGE 2-芳香酶轴的策略，最终目标是使与肥胖相关的芳香酶水平增加“正常化”。在SA 1中，我们将定义PGE 2，BRCA 1，组蛋白乙酰化和芳香化酶诱导之间的相互关系，基于我们的新数据暗示BRCA 1，Sirt-1和CBP/p300在PGE 2介导的芳香化酶诱导。在SA 2中，我们将使用基因敲除小鼠品系评估参与PGE 2合成或催化的酶考克斯- 1、mPGES-1或15-PGDH是否是MG和VF中芳香化酶表达和活性的决定因素。在SA 3中，我们将探索n-3脂肪酸调节PGE 2-芳香化酶途径的机制，因为n-3脂肪酸已被证明可以抑制PGE 2合成并预防实验性乳腺癌。最后，在SA 4中，我们将测试n-3脂肪酸单独或与考克斯-2抑制剂组合是否在肥胖小鼠的MG和VF中抑制炎症并降低体内芳香化酶水平。如果药理学或饮食方法破坏了肥胖-->炎症-->考克斯-->芳香化酶途径，这将代表一个重大的进步，并加强了解决女性类似问题的理由。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。 公共卫生相关性：我们已经表明，肥胖驱动脂肪组织中的炎症过程，导致雌激素合成酶芳香化酶的表达增加。在这里，我们建议测试药物或饮食方法，或两者结合，是否会破坏肥胖-炎症-环氧合酶-芳香酶途径。这项研究的积极发现将为评估减少激素受体阳性乳腺癌的新策略提供平台。

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.