|Role of Omega-3 Fatty Acids in the Risk and Treatment of Breast Cancer
|Abby L. Janos MS, RD
John V. Logomarsino PhD, RD, LD/N
|Topics in Clinical Nutrition
Volume 26 Number 3
Pages 246 - 256
More than one-third of cancers can be directly related to components in the diet. Breast cancer is sensitive to dietary changes and can be affected by consumption of omega-3 polyunsaturated fatty acids. Research studies show higher incidence and mortality rates of breast cancer in Western countries compared with Eastern countries because of variations in dietary practices. The ratio of omega-6 to omega-3 polyunsaturated fatty acids is essential when trying to reduce the incidence of breast cancer. Omega-6 polyunsaturated fatty acids may aid in the growth of mammary tumors, while omega-3 polyunsaturated fatty acids can reduce growth effects.
BREAST CANCER is the second leading cause of cancer mortality and is the most common cancer among women in the United States.1 Differences in dietary polyunsaturated fatty acid (PUFA) intake may account for a higher incidence rate of breast cancer in Western countries compared with Japan.2 The Western diet is high in omega-6 PUFAs, while the Japanese diet is higher in omega-3 PUFAs. The ratio of omega-6 to omega-3 PUFAs in the Western diet is 10:1 compared with that of the Japanese diet, which is 4:1.3 Omega-6 fatty acids, such as linoleic acid (LA) and arachidonic acid (AA), have been shown to have a stimulatory effect on cell proliferation in breast cancer studies. On the other hand, omega-3 fatty acids, such as [alpha]-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), have shown a growth-inhibitory effect.2 [alpha]-linolenic acid must be obtained through the diet and is endogenously converted to EPA and DHA in the body.4 EPA and DHA are structural phospholipids of cell membranes and alter membrane fluidity, cellular signaling, and cellular interaction. They are long-chain omega-3 PUFAs that have been shown to have growth-inhibitory effects on multiple types of tumors and cancers, including breast cancer.2 EPA and DHA also function in the regulation of the immune system by acting as precursors for the synthesis of eicosanoids, which are immunoregulatory metabolites. Omega-3 fatty acids are thought to decrease the function of proteins that inhibit apoptosis, thus limiting tumor growth.5 A summary of the mechanisms that link omega-3 fatty acids and the breast cancer carcinogenic process can be seen in Table 1.
||Table 1 Mechanisms that Link Omega-3 Fatty Acids and the Breast Cancer Carcinogenic Process
A MEDLINE and PubMed search was conducted to identify relevant research studies and articles using the following terminology: omega-3, docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, fatty acids, and breast cancer. The search was performed for all relevant articles published between the years 1996 and 2010. The exposure search strategy was to identify studies in relation to omega-3 fatty acid intake in the risk reduction and treatment of breast cancer.
The inhibition on breast cancer growth by omega-3 fatty acids: potential mechanisms
Omega-3 PUFAs appear to modulate breast cancer cell growth. One study was conducted to investigate the in vitro and in vivo anticancer cell effects of omega-3 PUFAs using the MCF-7 human breast cancer cell line.6 The in vitro study showed that DHA reduced DNA synthesis, apoptosis, and viability of MCF-7 human breast cancer cells. The in vivo study used mice that were injected with the MCF-7 human breast cancer cells while fed a 5% fish oil-supplemented diet for 6 weeks. Increased apoptosis, inhibition of proliferation, and reduction in MCF-7 growth was observed.6 Another study found that EPA inhibited MCF-7 cell growth by 30% and DHA inhibited MCF-7 cell growth by 54%.7 In addition, a third research study was performed on MCF-7 human breast cancer cells treated with DHA.8 They found that the omega-3 PUFAs induced apoptosis and also upregulated gene transcription of sulfate proteoglycan syndecan-1. Sulfate proteoglycan syndecan-1 has been shown to act as a tumor suppressor molecule by induction of apoptosis and inhibition of cell growth.8
The effect of omega-3 PUFAs on the suppression of breast cancer tumors may also be related to the inhibition of eicosanoid production from omega-6 fatty acids. Furthermore, research has also shown that the cancer inhibition by omega-3 fatty acids may result from increased lipid peroxidation.9,10 These molecular studies on cell differentiation and apoptosis are suggestive that omega-3 PUFAs are capable of modulating breast cancer cell growth.
Epidemiological studies: polyunsaturated fatty acids and breast cancer risk
Unhealthy dietary practices contribute to increased breast cancer rates in the United States compared with Japan. Migration studies show that women adopt the breast cancer risk of the new country of residence within one generation. One reason for this could be due to the ratio of omega-3 fatty acid to omega-6 fatty acid consumed in the diet rather than the total amount of dietary fat consumed.11 However, this is one of several contributing factors in the development of breast cancer, given that cancer is a multifactorial complex disease process.12
Epidemiological studies provide clear evidence that dietary fatty acids influence the reduction of growth and development of breast cancer. A summary of epidemiological studies is shown in Table 2. One case-control study examined the relationship between the risk of breast cancer and PUFA composition of breast adipose tissue. Breast adipose tissue can be altered by diet.2 Breast adipocytes are involved in the storage and release of essential fatty acids, which affect the differentiation, proliferation, and morphogenesis of breast cells. Improved omega-3 PUFA intake can potentially alter the content of breast adipocytes and decrease breast cancer risk. This study concluded that a high omega-6 PUFA intake may cause high breast cancer rates in the United States and that omega-3 PUFAs may have a protective effect and should be supplemented.2
||Table 2-a Epidemiological Studies on the Effect of Omega-3 Fatty Acids on Breast Cancer Risk
The fatty acid composition of the erythrocyte membrane may be related to breast cancer risk. A prospective study examined the interactions between dietary fatty acid intake and the erythrocyte membranes.13 The study showed that the fatty acid composition of the diet affects the composition of the erythrocyte by the endogenous synthesis and metabolism of fatty acid residues. The results of this study concluded that DHA consumed through fish in the diet was inversely associated with breast cancer risk.13
||Table 2-b Epidemiological Studies on the Effect of Omega-3 Fatty Acids on Breast Cancer Risk
||Table 2-c Epidemiological Studies on the Effect of Omega-3 Fatty Acids on Breast Cancer Risk
High intake of omega-3 fatty acids from fish is associated with reduced risk of breast cancer. Three research studies were conducted using validated food frequency questionnaires to determine dietary consumption of omega-3 fatty acids derived from fish in pre- and postmenopausal women. All 3 studies14-16 reported that a higher intake of omega-3 fatty acids from fish or fish oil was associated with a reduced risk of breast cancer. An additional research study concluded that women who consumed omega-3 fatty acids were 67% less likely to have nonproliferative fibrocystic conditions in the breast and 49% were less likely to develop breast cancer.17
DHA as an agent to improve the outcome of chemotherapy
Research studies have shown that dietary DHA is capable of making mammary tumors more sensitive to chemotherapy.18,19 The dose of conventional chemotherapy is still limited by adverse-effects such as damage to healthy tissues. Currently, there is a poor selection of anticancer drugs for advanced stages of breast cancer.18 Furthermore, individuals who have failed treatments have limited options available.
Dietary DHA increases tumor sensitivity to anticancer agents such as chemotherapy. One study used cultured breast cancer cells that were preenriched with DHA to show similar effects of their improved sensitivity to anticancer agents. The results showed a 78% reduction in cell growth.18 Another research study was conducted to examine the sensitivity of tumor cells to chemotherapy when membrane lipids were enriched with DHA. The researchers added 1.8 g/d of DHA to an anthracycline-based chemotherapy regimen in patients with breast cancer.19 Time to disease progression and overall survival rates were measured. They found statistically significant results showing that time to progression of disease was 8.7 months versus 3.5 months in the low-dose DHA compared with the high-dose DHA group (P = .02). The group that received the high dose of DHA also had significantly greater overall survival rates (38 months vs 8 months, P = .007).19
CLINICAL IMPLICATIONS AND RECOMMENDATIONS FOR HEALTH PROFESSIONALS
Although omega-3 PUFA supplementation may show promise in the risk reduction and treatment of breast cancer, it is important to take a balanced approach in recommending omega-3 fatty acid supplements. The risk of breast cancer is related to several nondietary risk factors, and omega-3 fatty acid status is only part of the clinical picture.12 Although research that shows the benefits of omega-3 fatty acid supplementation for patients diagnosed with breast cancer is advancing, 2 systematic reviews were not able to find significant associations between omega-3 fatty acid intake and the risk of various types of cancer.20,21 Further research is necessary before making a broad recommendation for omega-3 fatty acid supplementation for breast cancer risk reduction.
The American Dietetic Association recommends obtaining omega-3 fatty acids from dietary sources rather than from supplementation.22 Fatty fish is considered to be the best source of omega-3 PUFAs. Table 3 lists the most common food sources of omega-3 fatty acids including fruits and vegetables, specifically squash, raspberries, strawberries, broccoli, cauliflower, kidney beans, navy beans, green beans, romaine lettuce, and collard greens. Although total dietary fat has been associated with breast cancer development, it is important to focus on the type of fat as the major influence on cancer incidence.23 It is also important to note that high levels of saturated and trans fats in the diet can interfere with the conversion of ALA to EPA and DHA, so a diet that is low in these fats is advisable.24
||Table 3 Dietary Sources of Omega-6 (n-6) and Omega-3 (n-3) Polyunsaturated Fatty Acids
The Food and Nutrition Board of the Institute of Medicine has established adequate intakes (AI) as goals for individual intake of essential fatty acids.25 The AI for ALA is 1.6 g/d for adult men and 1.1 g/d for adult women. The Institute of Medicine has not assigned AIs for EPA or DHA because of a lack of strong evidence to make such recommendations. The Institute of Medicine has also established acceptable macronutrient distribution ranges (AMDRs) for total fat intake, omega-6 fatty acids, and omega-3 fatty acids. The AMDR for total fat is 20% to 35% of energy. The AMDR for the omega-6 fatty acid LA is 5% to 10% of energy and the AMDR for the omega-3 fatty acid ALA is 0.6% to 1.2% of energy. The risk for development of chronic disease increases when macronutrient intakes fall above or below AMDRs.25
According to the Federal Drug Administration, omega-3 fatty acids are generally recognized as safe when consumed in quantities up to 3 g/d.26 The 2010 Dietary Guidelines for Americans recommends eating 8 ounces of seafood per week to receive the benefits of EPA and DHA.27 Substituting olive or canola oil in the place of safflower, corn, or soybean oil for frying and baking will help decrease the consumption of omega-6 fatty acids.28Table 4 lists the omega-3 fatty acid concentrations of different oils, nuts, and seeds. Adopting a Mediterranean diet that increases fish consumption would result in a higher consumption of omega-3 fatty acids closer to the current health recommendations.29 In addition, increasing the consumption of fruits, vegetables, and whole grains will facilitate the intake of plant sources of omega-3 fatty acids. If consumers are unable to obtain the AI from diet, supplementation should be considered. The research studies presented all showed positive effects of supplementation but there are not dietary guidelines set for the breast cancer population. There simply needs to be more human case-control studies to establish guidelines for supplementation.
||Table 4 Omega-3 Fatty Acid Content of Oils, Nuts, and Seeds and Amounts Needed to Meet the Adequate Intakes for Both Men and Women According to the IOM Recommendations
For some individuals, there may be concerns about consumption of omega-3 PUFA and fish oil supplements. Fish oils and EPA prolong bleeding time and individuals who use anticoagulant therapy should be monitored. Fish oil consumption is not recommended 7 to 14 days before surgery because of the increased risk of bleeding.30 Because fish oil may produce a small reduction in blood pressure, there may be an additive effect with drugs used to treat hypertension.31 Consumption of very high levels of long-chain omega-3 PUFAs (>10 g/d) has been associated with increased risk of hemorrhagic stroke.32 Omega-3 fatty acids can slightly increase low-density lipoprotein cholesterol levels when taken in high doses. However, the favorable effects outweigh the modest increase in low-density lipoprotein levels.33 When EPA and DHA are consumed in amounts greater than 3 g/d, the risk of bleeding is increased. These symptoms generally subside once dosages are lowered.34 Fishy eructation is a common phenomenon among fish oil users. Fish oil capsules may also cause gastrointestinal distress, including diarrhea, heartburn, indigestion, nausea, and abdominal bloating.31,34
FUTURE RESEARCH DIRECTIONS
There is a large quantity of literature that describes the effects of omega-3 PUFAs on tumor behavior in animal and cell models.6-10,18,19 However, these research models are heterogeneous in terms of the models and carcinogens used. They also vary in dose, timing, and duration of exposure to omega-3 PUFAs. Chemoprevention trials should focus on identification of a recommended dosage for supplementation of omega-3 fatty acids to achieve maximum biological activity and increase tumor sensitivity. If the models were designed to be more homogeneous in nature, the research standards might lead to more efficient studies in this area.
There is relatively little information about the effects of fatty acids on breast cancer in early stages of life. Large-scale intervention studies such as cohorts can be useful to identify diet from early life through adulthood to study the incidence of cancer. Future research should to be focused in the areas of prevention rather than treatment of cancer and metastatic disease. This data would be useful in identifying optimal methods and timing of nutrition intervention.35 Many studies have focused their efforts in the laboratory and it is vital to bring these interventions into the clinical practice. Because of the lack of controlled studies, there needs to be an aggressive step forward to conduct long-term studies on the effects of omega-3 PUFAs on breast cancer risk reduction to determine appropriate supplementation guidelines.35
An additional area of future research would be to examine the effects of omega-3 PUFAs on oncogene expression in human cancer studies. There has been a great deal of research conducted using olive oil, rich in monounsaturated fatty acids, and human cancer cells to understand the mechanisms of how oncogenes can be regulated by its components.36-40 Using the monounsaturated fatty acids oleic acid, researchers have been able to suppress the expression and activity of the human epidermal growth factor receptor 2 oncogene in human cancer studies.36 However, more research and focus in the area of oncogene expression and omega-3 PUFAs has the potential to yield some appealing results.
EPA and DHA have been shown to decrease the growth of human breast cancer cells in human, animal, and cellular research. The incidence and mortality rates of breast cancer can be significantly reduced if adequate intake and supplementation guidelines are developed for health and nutrition professionals. However, further research is needed to support the development of evidenced-based nutrition guidelines for the recommended intake of both dietary omega-3 fatty acids and supplementation in the risk reduction and treatment of breast cancer.
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breast cancer; docosahexaenoic acid; eicosapentaenoic acid; fatty acids; omega-3