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：
8702094
负责人：
ANDREW Jess DANNENBERG
金额：
$ 34.02万
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/8702094
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 Diet 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 abstracting 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

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.

项目摘要/摘要肥胖症是绝经后激素受体（HR）阳性乳腺癌的确定危险因素女性。这种增加的风险被认为部分归因于脂肪增加的雌激素产生组织，因为脂肪组织是雌激素合成酶芳香酶POST的主要作用部位高潮。鉴于当前肥胖的流行，有迫切需要开发基于机制的减少该人群中癌症风险的策略。雌激素剥夺通常是使用用于预防乳腺癌和治疗的方法，但是Serm和芳香酶抑制剂均具有限制其广泛使用预防的重要副作用。我们通过针对驱动增加芳香化酶表达的途径可能会抑制雌激素过量生产脂肪组织，包括乳房，因此降低了超重中HR阳性乳腺癌的风险和肥胖。在这方面重要的是，已经建立了环氧酶（COX）衍生的关键作用前列腺素E2（PGE2）在刺激编码芳香化酶的CYP19基因的转录中。我们报告说，乳腺（MG）中的COX-2过表达导致PGE2产生增加和芳香化酶表达升高。令人惊讶的是，我们现在发现严重的炎症，升高 Cox-2表达和芳香酶水平增加在小鼠中的MG和内脏脂肪（VF）中出现肥胖模型。这些令人兴奋的发现提出了与肥胖有关的炎症的非常真实的可能性 MG和VF的变化都会导致芳香化酶活性升高，从而增加HR-的风险阳性乳腺癌。因此，该提案的目的是评估破坏蛛网的策略酸代谢，从而抑制PGE2->芳香酶轴，其最终目标是“正常化” 与肥胖相关的芳香酶的水平增加。在SA1中，我们将定义相互关系基于我们的新数据，PGE2，BRCA1，组蛋白乙酰化和芳香化酶诱导之间 PGE2介导的芳香化酶诱导中的BRCA1，SIRT-1和CBP/P300。在SA2中，我们将评估Cox-是否 1，MPGES-1或15-PGDH，参与PGE2合成或分解代谢的酶是决定因素使用基因敲除小鼠菌株在MG和VF中的芳香化酶表达和活性。在SA3中，我们将探索 N-3脂肪酸调节PGE2->芳香酶途径的机制，因为N-3脂肪酸具有被证明可以抑制PGE2合成并预防实验性乳腺癌。最后，在SA4中将测试N-3脂肪酸是单独或与COX-2抑制剂结合的，抑制炎症并减少肥胖小鼠的Mg和VF中的体内芳香化酶水平。如果是药理或饮食方法破坏肥胖 - >炎症 - > cox->芳香酶途径，这将代表一个重大的进步并加强解决女性类似问题的理由。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。