Omega-3 Fatty Acid Modulation of Obesity-Induced Aromatase Expression

Omega-3 脂肪酸对肥胖诱导的芳香酶表达的调节

• 批准号: 9035932
• 负责人: Andrew Jacob Brenner
• 金额: $ 17.68万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-24 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035932
• 关键词: Aromatase; Aromatase Inhibitors; Biological Markers; Biology; Breast Cancer Cell; Breast Cancer Patient; Cancer Prognosis; Clinical; Clinical Research; Comorbidity; Data; Development; Diagnosis; Dinoprostone; Disease; Disease Progression; Eicosanoids; Emergency Department patient; Epithelial; Estrogen Receptor alpha; Fish Oils; Foundations; Future; Gene Expression; Growth; Hormones; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Intervention; Intervention Studies; Intervention Trial; Leptin; Malignant Neoplasms; Mammary gland; Mediating; Non obese; Non-Steroidal Anti-Inflammatory Agents; Obesity; Omega-3 Fatty Acids; Outcome; PTGS2 gene; Patient-Focused Outcomes; Patients; Phase; Phenotype; Physiological; Postmenopause; Premenopause; Preventive; Production; Prognostic Marker; Prostaglandin-Endoperoxide Synthase; Publishing; Recurrence; Reporting; Research Personnel; Resistance development; Retrospective Studies; Signal Transduction; Specimen; Staging; TNF gene; Tamoxifen; Testing; Woman; adipokines; arm; base; cancer cell; comparative; cyclooxygenase 2; cytokine; disorder later incidence prevention; fatty acid supplementation; hormone therapy; improved; innovation; malignant breast neoplasm; metabolomics; mortality; novel; patient population; pre-clinical; prevent; prospective; public health relevance; resistance mechanism; response; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Over the last decade, a large body of evidence has established that obesity is associated with a worse breast cancer prognosis for both pre- and postmenopausal women. There are several mechanism(s) which have been proposed for promoting this effect, with recent evidence suggesting that the obese state is associated with changes in the biology of the disease, promoting a more aggressive phenotype. Clinically, obesity correlates with worse outcome on hormone therapy agents, most notably aromatase inhibitors (AI). Our group, as well as others, has demonstrated that obesity promotes increased local aromatase expression in the mammary gland. Our preliminary studies suggest that this induction is mediated primarily through cyclooxygenase (Cox)-derived prostaglandin E2 (PGE2), that this induction is associated with increased estrogen receptor α (ERα) activity in mammary epithelial cancer cells, and most importantly, that regular use of NSAIDs may reduce the rate of recurrence on AIs by half. These data suggest that interventions that suppress COX-2 PGE2 production may provide significant benefit for the obese ER+ patient. Omega-3 fatty acids have demonstrated anti-cancer benefit through multiple mechanisms, including suppression of inflammation-related signaling. The omega-3 PUFAs serve as competitive substrates for COX- 2 activity, resulting in suppressed PGE2 production. Importantly, our preliminary data suggest that at physiological relevant levels DHA is able to inhibit obesity-induced PGE2 production in vitro. Our exceptional collaborative team of investigators will use highly integrated pre-clinical and clinical studies to test the novel hypothesis that omega-3 fatty acid supplementation can be used to improve response to AIs in the obese postmenopausal breast cancer patient population and prevent many of the tumor-promoting effects of obesity. The results of this study could have an immediate impact on patient outcomes by transitioning directly into a larger intervention trial evaluating both the proposed mechanism of resistance and the use of omega-3 fatty acid supplements to improve response.

 描述（由申请人提供）：在过去的十年中，大量证据表明，肥胖与绝经前和绝经后女性的乳腺癌预后较差有关，已经提出了几种促进乳腺癌预后的机制。最近的证据表明，肥胖状态与疾病的生物学变化有关，从而促进更具侵袭性的表型。在临床上，肥胖与激素治疗药物（最显着的芳香酶抑制剂（AI））的不良结果相关。小组以及其他人已经证明，肥胖会促进乳腺中局部芳香酶表达的增加，我们的初步研究表明，这种诱导主要是通过环氧合酶（Cox）衍生的前列腺素 E2（PGE2）介导的，并且这种诱导与相关。乳腺癌细胞中雌激素受体 α (ERα) 活性增加，最重要的是，经常使用 NSAID 可以将 AI 的复发率降低一半。这些数据表明，抑制的干预措施。 COX-2 PGE2 的产生可能为肥胖 ER+ 患者带来显着益处，Omega-3 脂肪酸已通过多种机制证明具有抗癌功效，包括抑制炎症相关信号传导。Omega-3 PUFA 可作为 COX- 的竞争性底物。重要的是，我们的初步数据表明，在生理相关水平上，DHA 能够在体外抑制肥胖诱导的 PGE2 产生。临床前和临床研究测试了新的假设，即补充 omega-3 脂肪酸可用于改善肥胖绝经后乳腺癌患者群体对 AI 的反应，并预防肥胖的许多促肿瘤作用。研究可以直接过渡到更大规模的干预试验，评估所提出的耐药机制和使用 omega-3 脂肪酸补充剂来改善反应，从而对患者的治疗结果产生立竿见影的影响。