Contract HHSN261201200034I - Clinical Prevention Agent Development Program: Early Phase Clinical ResearchPeriod of Performance: 9/24/2012 - 9/23/2017Task Order Title: A Multicenter Phase II Stud

合同 HHSN261201200034I - 临床预防剂开发计划：早期临床研究执行周期：2012 年 9 月 24 日 - 2012 年 9 月 23 日任务订单标题：多中心 II 期研究

• 批准号: 8948544
• 负责人: POWEL BROWN
• 金额: $ 68.56万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-03-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8948544
• 关键词: Acceleration; Adipocytes; Adipose tissue; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Aromatase; Benign; Biological Markers; Blood Circulation; Breast; Breast Diseases; Budgets; Clinical; Contracts; Data; Dental crowns; Diet; Dietary Factors; Dietary Intervention; Dinoprostone; Docosahexaenoic Acids; Eligibility Determination; Enrollment; Enzymes; Epidemiologic Studies; Estrogens; Evaluation; Fatty Acids; Fatty acid glycerol esters; Fish Oils; General Population; Goals; Gonadal Steroid Hormones; Growth Factor; Hormone Receptor; Inflammation; Inflammation Mediators; Institution; Interleukin-6; Lesion; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Medicine; Mus; Necrosis; Obesity; Omega-3 Fatty Acids; Overweight; PTGS2 gene; Participant; Patients; Performance; Phase; Postmenopause; Premalignant; Prevention; Production; Program Development; Property; Protocols documentation; RNA; Recording of previous events; Risk; Risk Factors; Signal Transduction; Source; Specimen; Structure; Tumor Necrosis Factor-alpha; Update; Validation; Visceral; Woman; cancer risk; feeding; macrophage; malignant breast neoplasm; mortality; mouse model; outcome forecast; patient population; phase 2 study; response; transcription factor; tumor progression

¬Obesity is a risk factor for hormone receptor (HR)-positive breast cancers and particular subtypes of HR-negative breast cancers, such as basal-like cancers. Adiposity may increase breast cancer risk through multiple mechanisms, including elevating post-menopausal production of sex-steroids, growth factors and inflammation Obesity is associated with subclinical inflammation in adipose tissue. Data from mouse models and studies of women, suggest that obesity is associated with formation “crown-like structures (CLS)”, which are composed of macrophages encircling necrotic adipocytes. These macrophages produce a variety of pro-inflammatory mediators. In obese women, increased levels of pro-inflammatory mediators are commonly found in the circulation and may contribute to breast cancer progression and mortality. In diet and genetically induced mouse models of obesity, CLS form in the adipose tissue of the mouse mammary gland and visceral fat. Importantly, the presence of CLS was associated with increased levels of several pro-inflammatory mediators (TNF-α, IL-1β, Cox-2, PGE2) and activation of the NF-κB transcription factor. These changes were paralleled by elevated levels of aromatase, the rate-limiting enzyme for estrogen synthesis, in both the mammary gland and visceral fat. Independent validation of the associations between obesity, CLS and inflammation in breast adipose and expression of pro-inflammatory mediators (including IL-6) was recently provided by a group from UNC, Chapel Hill who studied women undergoing reduction mammoplasty specimens (n=74). Overall, these results support the existence of an obesity-inflammation-aromatase axis that may contribute to the increased risk of breast cancer in obese women, and a worse prognosis. Docosahexaenoic acid, an omega-3 fatty acid in fish oil, can suppress levels of inflammatory mediators including TNF-α and COX-2. In feeding studies, it has been shown that treatment with DHA can also reduce levels of aromatase in the mouse mammary gland. Consistent with these findings, diets rich in fish oil, a source of omega-3 fatty acids, have been associated with a reduced risk of a number of malignancies including breast cancer and similar diets protect against experimentally induced mammary cancer in animals. In the general population, omega-3 fatty acid supplements, such as DHA are widely used but the underlying mechanisms of action are incompletely understood. Consistent with targeted therapies, dietary factors including omega-3 fatty acids may only be beneficial in subsets of patients. This would make it difficult to detect a consistent clinically important signal in epidemiological studies. It is likely that nutritional interventions like medicines will need to be personalized. Taken together, these observations emphasize the importance of determining whether DHA possesses anti-inflammatory properties in the breast tissue of overweight and obese women.

•肥胖是同性受体（HR）阳性乳腺癌和HR阴性乳腺癌的特定亚型的危险因素，例如碱性癌。脂肪性可能通过多种机制增加乳腺癌的风险，包括升高性行为 - 类固醇，生长因子和炎症肥胖症与脂肪组织中亚临床炎症有关。来自小鼠模型和女性研究的数据表明，肥胖与形成“冠状结构（CLS）”有关，这些结构（CLS）由包围坏死脂肪细胞的巨噬细胞组成。这些巨噬细胞产生各种促炎性介体。在肥胖女性中，循环中通常发现促炎性介质的水平增加，并可能导致乳腺癌的进展和死亡率。在饮食和遗传诱导的肥胖小鼠模型中，在小鼠乳腺和内脏脂肪的脂肪组织中形成CLS。重要的是，CLS的存在与几个促炎性介质（TNF-α，IL-1β，COX-2，PGE2）的水平增加以及NF-κB转录因子的激活有关。这些变化与芳香酶的水平升高（乳腺和内脏脂肪的雌激素合成的速率限制酶）相反。最近，来自UNC的一组教堂，研究了接受还原乳腺成形术标本的妇女（n = 74）的妇女，对乳腺脂肪和促炎性介质的表达（包括IL-6）的肥胖，CLS和炎症之间的关联的独立验证（包括IL-6）。总体而言，这些结果支持肥胖 - 炎症 - 芳香酶轴的存在，可能导致肥胖女性乳腺癌的风险增加，并且预后较差。 鱼油中的omega-3脂肪酸二十六烯酸可以抑制包括TNF-α和COX-2在内的炎症介质水平。在喂养研究中，已经表明，用DHA治疗还可以降低小鼠乳腺中的芳香酶水平。与这些发现一致，富含鱼油的饮食是omega-3脂肪酸的来源，与许多恶性肿瘤的风险降低有关，包括乳腺癌和类似的饮食，可以防止动物中的实验诱导的乳腺癌。在一般人群中，omega-3脂肪酸补充剂（例如DHA）被广泛使用，但基本的作用机制却不完全理解。与有针对性的疗法一致，包括omega-3脂肪酸在内的饮食因素可能仅对患者子集有益。这将使在流行病学研究中难以检测一致的临床重要信号。可能需要个性化药物的营养干预措施。综上所述，这些观察结果强调了确定DHA在超重和肥胖妇女的乳房组织中是否具有抗炎特性的重要性。