IGF::OT::IGF A MULTICENTER PHASE II STUDY OF DOCOSAHEXAENOIC ACID IN PATIENTS WITH A HISTORY OF BREAST CANCER, PREMALIGNANT LESIONS, OR BENIGN BREAST DISEASE

肥胖是激素受体（HR）阳性乳腺癌和特定亚型的HR阴性乳腺癌（如基底样癌）的风险因素。肥胖可能通过多种机制增加乳腺癌的风险，包括增加绝经后性类固醇、生长因子和炎症的产生。来自小鼠模型和女性研究的数据表明，肥胖与“冠状结构（CLS）"的形成有关，所述冠状结构由包围坏死脂肪细胞的巨噬细胞组成。这些巨噬细胞产生多种促炎介质。在肥胖女性中，促炎介质水平的增加通常存在于循环中，并可能导致乳腺癌进展和死亡率。在饮食和遗传诱导的肥胖小鼠模型中，CLS在小鼠乳腺和内脏脂肪的脂肪组织中形成。重要的是，CLS的存在与几种促炎介质（TNF-α、IL-1β、考克斯-2、PGE 2）水平的升高和NF-κB转录因子的激活相关。这些变化被乳腺和内脏脂肪中芳香化酶（雌激素合成的限速酶）水平升高所掩盖。最近，来自查佩尔山的一个研究小组提供了肥胖、CLS和乳房脂肪炎症与促炎介质（包括IL-6）表达之间相关性的独立验证，该研究小组研究了接受乳房缩小术标本的女性（n=74）。总的来说，这些结果支持肥胖-炎症-芳香化酶轴的存在，这可能导致肥胖女性患乳腺癌的风险增加，预后更差。二十二碳六烯酸是鱼油中的一种ω-3脂肪酸，可以抑制炎症介质的水平，包括TNF-α和考克斯-2。在喂养研究中，已经表明用DHA治疗也可以降低小鼠乳腺中芳香酶的水平。与这些发现相一致的是，富含鱼油（ω-3脂肪酸的来源）的饮食与包括乳腺癌在内的许多恶性肿瘤的风险降低有关，并且类似的饮食可以防止动物实验诱导的乳腺癌。在一般人群中，omega-3脂肪酸补充剂，如DHA被广泛使用，但其潜在的作用机制尚不完全清楚。与靶向治疗一致，包括omega-3脂肪酸在内的饮食因素可能仅对患者亚群有益。这将使得在流行病学研究中难以检测到一致的临床重要信号。营养干预措施，如药物，可能需要个性化。总之，这些观察结果强调了确定DHA是否在超重和肥胖女性的乳房组织中具有抗炎特性的重要性。

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.