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

 描述(由申请人提供)：在过去的十年里，大量证据表明，肥胖与绝经前和绝经后女性乳腺癌预后较差有关。有几种机制(S)提出了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)。我们的团队以及其他人已经证明，肥胖会促进乳腺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(PGE_2)介导的，这种诱导与乳腺上皮癌细胞中雌激素受体α(ER-α)活性的增加有关，最重要的是，定期使用非甾体抗炎药可能会将AIS的复发率降低一半。这些数据表明，抑制COX-2 PGE2产生的干预措施可能会为肥胖的ER+患者提供显著的好处。Omega-3脂肪酸通过多种机制显示出抗癌的益处，包括抑制与炎症有关的信号。Omega-3多不饱和脂肪酸作为COX-2活性的竞争性底物，导致PGE2的产生受到抑制。重要的是，我们的初步数据表明，在生理相关水平上，DHA在体外能够抑制肥胖诱导的PGE2的产生。我们出色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这一新假设，即补充omega-3脂肪酸可以用来改善肥胖绝经后乳腺癌患者群体对AIS的反应，并防止肥胖的许多促癌作用。这项研究的结果可以直接过渡到一项更大的干预试验，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，从而对患者的预后产生直接影响。

 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.