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：
8881112
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/8881112
关键词：
Address Adipose tissue Adverse effects Androgens Anti-Inflammatory Agents Arachidonic Acids Aromatase Aromatase Inhibitors BRCA1 gene Breast Breast Cancer Patient Breast Cancer Prevention CYP19A1 gene 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 Metastatic breast cancer 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 dietary approach 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.

项目概要/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女性。这种风险增加被认为部分归因于脂肪中雌激素产量的增加组织，因为脂肪组织是雌激素合成酶芳香酶后的主要作用部位更年期。鉴于当前肥胖的流行，迫切需要开发基于机制的方法降低这一人群癌症风险的策略。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 和芳香酶抑制剂都具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量产生脂肪组织，包括乳房，从而降低超重者患 HR 阳性乳腺癌的风险和肥胖。重要的是，在这方面，环氧合酶 (COX) 衍生的关键作用已被确定。前列腺素 E2 (PGE2) 刺激编码芳香酶的 CYP19 基因的转录。我们已经报道，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，我们现在发现显着的炎症、升高的小鼠 MG 和内脏脂肪 (VF) 中均出现 COX-2 表达和芳香酶水平升高肥胖模型。这些令人兴奋的发现提出了一种非常现实的可能性，即与肥胖相关的炎症 MG 和 VF 的变化会导致芳香酶活性升高，从而增加 HR- 风险阳性乳腺癌。因此，本提案的目标是评估破坏花生四烯酸的策略酸代谢，从而抑制 PGE2-> 芳香酶轴，最终目标是“正常化” 与肥胖相关的芳香酶水平升高。在SA1中，我们将定义相互关系 PGE2、BRCA1、组蛋白乙酰化和芳香酶诱导之间的关系，基于我们涉及的新数据 PGE2 介导的芳香酶诱导中的 BRCA1、Sirt-1 和 CBP/p300。在 SA2 中，我们将评估 COX- 1、mPGES-1或15-PGDH，参与PGE2合成或分解代谢的酶，是PGE2的决定因素使用敲除小鼠品系观察 MG 和 VF 中芳香酶的表达和活性。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可以抑制炎症并减少炎症肥胖小鼠 MG 和 VF 体内芳香酶水平。如果通过药物或饮食方法破坏肥胖->炎症->COX->芳香酶途径，这将代表一个重大进步并强化解决妇女类似问题的理由。总的来说，这次调查的结果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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Caloric restriction reverses obesity-induced mammary gland inflammation in mice.

热量限制可逆转肥胖引起的小鼠乳腺炎症。

DOI：
发表时间：
2013-04
期刊：
影响因子：
0
作者：
Bhardwaj, Priya;Du, Baoheng;Zhou, Xi Kathy;Sue, Erika;Harbus, Michael D;Falcone, Domenick J;Giri, Dilip;Hudis, Clifford A;Kopelovich, Levy;Subbaramaiah, Kotha;Dannenberg, Andrew J
通讯作者：
Dannenberg, Andrew J

Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women.

COX-2 和前列腺素 E2 水平升高导致肥胖女性发炎乳腺组织中芳香酶表达升高。

DOI：
发表时间：
2012-04
期刊：
影响因子：
28.2
作者：
Subbaramaiah, Kotha;Morris, Patrick G;Zhou, Xi Kathy;Morrow, Monica;Du, Baoheng;Giri, Dilip;Kopelovich, Levy;Hudis, Clifford A;Dannenberg, Andrew J
通讯作者：
Dannenberg, Andrew J

Genetic deletion of microsomal prostaglandin E synthase-1 suppresses mouse mammary tumor growth and angiogenesis.

微粒体前列腺素 E 合酶 1 的基因缺失可抑制小鼠乳腺肿瘤生长和血管生成。

DOI：
发表时间：
2013-10
期刊：
影响因子：
2.9
作者：
Howe, Louise R;Subbaramaiah, Kotha;Kent, Claire V;Zhou, Xi K;Chang, Sung;Hla, Timothy;Jakobsson, Per;Hudis, Clifford A;Dannenberg, Andrew J
通讯作者：
Dannenberg, Andrew J

Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1.

Pioglitazone 是一种 PPARγ 激动剂，抑制 CYP19 转录：15-羟基前列腺素脱氢酶和 BRCA1 参与的证据。

DOI：
发表时间：
2012-10
期刊：
影响因子：
0
作者：
Subbaramaiah, Kotha;Howe, Louise R;Zhou, Xi Kathy;Yang, Peiying;Hudis, Clifford A;Kopelovich, Levy;Dannenberg, Andrew J
通讯作者：
Dannenberg, Andrew J

Identification of macrophage extracellular trap-like structures in mammary gland adipose tissue: a preliminary study.

乳腺脂肪组织中巨噬细胞胞外陷阱样结构的鉴定：初步研究。