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.