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

针对肥胖-炎症-COX-芳香酶轴来降低乳腺癌风险

基本信息

批准号：
8230379
负责人：
ANDREW Jess DANNENBERG
金额：
$ 35.07万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230379
关键词：
Address Adipose tissue Adverse effects Androgens Anti-Inflammatory Agents Arachidonic Acids Aromatase Aromatase Inhibitors BRCA1 gene Breast Breast Cancer Prevention CYP19A1 gene Cancer Patient Catabolism Chemoprevention Chemopreventive Agent Climacteric Consumption Coxibs Cultured Cells Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Dietary Intervention Dinoprostone Dose EP300 gene Enzymes Epidemic Estrogen Receptors Estrogens Experimental Models Fatty acid glycerol esters Fish Oils Functional disorder Genes Genetic Transcription Goals Histone Acetylation Histone Code Histone Deacetylase Hormone Receptor Hormones In Vitro Incidence Inflammation Inflammatory Knockout Mice Lipids Mammary gland Mediating Menopause Metabolism Mouse Strains Mus Obese Mice Obesity Omega-3 Fatty Acids Overweight Pathogenesis Pathway interactions Peripheral Population Postmenopause Prevention Process Production Property Prophylactic treatment Prostaglandin-Endoperoxide Synthase Proteins Reaction Regimen Reporting Research Risk Risk Factors Selective Estrogen Receptor Modulators Site Testing Tissues Visceral Woman base cancer risk cancer therapy cardiovascular risk factor celecoxib cyclooxygenase 1 cyclooxygenase 2 deprivation in vivo insight malignant breast neoplasm mouse PGE synthase 1 mouse model novel overexpression tumor tumor growth

项目摘要

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.

描述（由申请人提供）：肥胖是绝经后妇女患激素受体（HR）阳性乳腺癌的既定危险因素。这种风险增加被认为部分归因于脂肪组织雌激素产生的增加，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。鉴于当前肥胖症的流行，迫切需要制定基于机制的策略来降低该人群的癌症风险。剥夺雌激素是乳腺癌预防和治疗的常用方法，但 SERM 和芳香酶抑制剂均具有显着的副作用，限制了其广泛用于预防。我们假设，通过靶向驱动芳香酶表达增加的途径，将有可能抑制脂肪组织（包括乳房）中雌激素的过量产生，从而降低超重和肥胖者患 HR 阳性乳腺癌的风险。重要的是，在这方面，已经确定了环氧合酶 (COX) 衍生的前列腺素 E2 (PGE2) 在刺激编码芳香酶的 CYP19 基因转录中的关键作用。我们报道，乳腺 (MG) 中 COX-2 过度表达会导致 PGE2 产量增加和芳香酶表达升高。引人注目的是，我们现在发现肥胖小鼠模型的 MG 和内脏脂肪 (VF) 中均出现明显的炎症、COX-2 表达升高和芳香酶水平升高。这些令人兴奋的发现提出了一种非常现实的可能性，即 MG 和 VF 中与肥胖相关的炎症变化会导致芳香酶活性升高，从而增加 HR 阳性乳腺癌的风险。因此，本提案的目标是评估扰乱花生四烯酸代谢的策略，从而抑制 PGE2--> 芳香酶轴，最终目标是使与肥胖相关的芳香酶水平升高“正常化”。在 SA1 中，我们将根据 BRCA1、Sirt-1 和 CBP/p300 在 PGE2 介导的芳香酶诱导中的新数据，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，我们将使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，我们将探讨 n-3 脂肪酸调节 PGE2→芳香酶途径的机制，因为 n-3 脂肪酸已被证明可以抑制 PGE2 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 抑制剂联合使用是否能够抑制肥胖小鼠 MG 和 VF 体内的炎症并降低芳香酶水平。如果药理学或饮食方法破坏了肥胖-->炎症-->COX-->芳香酶途径，这将代表着重大进步，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。公共健康相关性：我们已经证明，肥胖会驱动脂肪组织中的炎症过程，导致雌激素合成酶芳香酶的表达增加。在这里，我们建议测试药物或饮食方法或其组合是否会破坏肥胖->炎症->环氧合酶->芳香酶途径。这项研究的积极结果将为评估减少激素受体阳性乳腺癌的新策略提供一个平台。