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

 描述（由申请人提供）：在过去的十年中，大量的证据表明，肥胖与绝经前和绝经后妇女乳腺癌预后不良有关。已经提出了几种促进这种效应的机制，最近的证据表明肥胖状态与疾病生物学的变化有关，促进了更具侵略性的表型。在临床上，肥胖与激素治疗药物的不良结果相关，最明显的是芳香酶抑制剂（AI）。我们的研究小组以及其他研究小组已经证明，肥胖会促进乳腺局部芳香化酶表达的增加。我们的初步研究表明，这种诱导作用主要是通过环氧合酶（考克斯）衍生的前列腺素E2（PGE 2）介导的，这种诱导作用与乳腺上皮癌细胞中雌激素受体α（ERα）活性增加有关，最重要的是，定期使用NSAID可将AI的复发率降低一半。这些数据表明，干预措施，抑制考克斯-2 PGE 2的生产可能会为肥胖ER+患者提供显着的好处。Omega-3脂肪酸通过多种机制表现出抗癌益处，包括抑制炎症相关信号。ω-3 PUFA作为考克斯- 2活性的竞争性底物，导致抑制PGE 2的产生。重要的是，我们的初步数据表明，在生理相关水平的DHA能够抑制肥胖诱导的PGE 2体外生产。我们杰出的合作研究团队将使用高度整合的临床前和临床研究来测试新的假设，即omega-3脂肪酸补充剂可用于改善肥胖绝经后乳腺癌患者人群对AI的反应，并预防肥胖的许多肿瘤促进作用。这项研究的结果可能会对患者的结果产生直接影响，直接过渡到一个更大的干预试验，评估拟议的耐药机制和使用omega-3脂肪酸补充剂来改善反应。

 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.