Contract HHSN261201200034I - Clinical Prevention Agent Development Program: Early Phase Clinical ResearchPeriod of Performance: 9/24/2012 - 9/23/2017Task Order Title: A Multicenter Phase II Stud

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¬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.