Abstract and Introduction
Women with evidence of high intake ratios of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid have been found to have a reduced risk of breast cancer compared with those with low ratios in some but not all case–control and cohort studies. If increasing EPA and DHA relative to arachidonic acid is effective in reducing breast cancer risk, likely mechanisms include reduction in proinflammatory lipid derivatives, inhibition of nuclear factor-κB-induced cytokine production, and decreased growth factor receptor signaling as a result of alteration in membrane lipid rafts. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints are underway but final results of these trials are currently unavailable. EPA and DHA supplementation is also being explored in an effort to help prevent or alleviate common problems after a breast cancer diagnosis, including cardiac and cognitive dysfunction and chemotherapy-induced peripheral neuropathy. The insulin-sensitizing and anabolic properties of EPA and DHA also suggest supplementation studies to determine whether these omega-3 fatty acids might reduce chemotherapy-associated loss of muscle mass and weight gain. We will briefly review relevant omega-3 fatty acid metabolism, and early investigations in breast cancer prevention and survivorship.
Although the predominant driving force in breast carcinogenesis has been thought to be hormonal, cytokine production and inflammation are also being recognized as important in breast cancer development and progression.[1,2] A progressive increase in activated macrophages and T cells is observed between normal breast tissue, proliferative breast disease, and breast cancer.[3,4] The stimulus for the increase in inflammatory cell infiltration observed with proliferative breast disease and breast cancer is unknown but probably has varying etiologies including immunogenic gene alterations in epithelial cells, reaction to breakdown of basement membrane components, and for obese women excess cytokine production from dysfunctional adipocytes.
The long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are important in generating bioactive lipid mediators important in inflammation resolution. As key components of phospholipid membranes and lipid rafts that serve to organize or separate molecules, these fatty acids also affect cell signaling thought to impact breast carcinogenesis.[8–12] The ability of long-chain omega-6 fatty acids to modulate inflammation and other physiologic processes is dependent on concomitant levels of the proinflammatory omega-6 arachidonic acid (AA) as well as an individual's genetic makeup governing lipid metabolism.[13–16]
Interest in the use of supplementary omega-3 fatty acids to reduce risk of cancer and other chronic debilitating conditions, including cardiovascular disease and cognitive impairment, stems from several longstanding avenues of investigation: 1) an increased incidence of breast cancer and heart disease in western societies with low omega-3:omega-6 fatty acid intake ratios; 2) a very low incidence of these two conditions in populations with high marine omega-3 fatty acid intake (Japan and natives of Alaska and Greenland); 3) a dramatic increase in the incidence of breast cancer and cardiovascular disease in cohorts from low-incidence populations who migrate to western countries and/or adopt a western diet;[15,17] and 4) the demonstrated importance of adequate DHA in retinal and brain development and cognitive function.[18,19]
Although the ideal total omega 3:omega-6 intake ratio has not been defined, a ratio approaching 1:1 or 1:2 similar to that of precivilized man is generally accepted as associated with a low incidence of diseases characterized by chronic inflammation, and therefore is desirable.[16,20] By the early 1900s the omega 3:omega-6 intake ratio in the United States was estimated at 1:5, probably due to the high dietary content of corn oil products and corn-fed animals. Today, largely due to the >1,000-fold increase in use of soybean oil in the last several decades, the dietary omega 3:omega-6 intake ratio is now 1:10 or lower.[16,21] Although much of the imbalance is probably due to the increase in omega-6 consumption, it has been suggested that the most practical remedy may actually be to increase long-chain or marine omega-3 intake rather than to attempt to markedly reduce omega-6 intake.[22,23]
We will briefly review omega-3 and omega-6 fatty acid metabolism and function, preclinical mechanistic and prevention studies, as well as selected case–control and prospective cohort studies, and ongoing trials relevant to breast cancer prevention. Reports dealing with omega-3 fatty acids and breast cancer recurrence as well as other relevant survivorship topics including insulin resistance and obesity, cardiovascular disease and cognition will also be discussed.
Breast Cancer Res. 2015;17(62) © 2015 BioMed Central, Ltd.
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