Do omega-3 fatty acids reduce the risk of breast cancer in postmenopausal obese women?

KEYWORDS:

• Obesity and breast cancer
• breast cancer prevention
• omega-3 fatty acids
• DHA
• DHA and dietary energy restriction
• DHA and anti-estrogens

1. Introduction

Strong evidence indicates that excess body weight increases the risk of postmenopausal breast cancer by creating a hyperestrogenic and pro-inflammatory milieu systemically and locally in the mammary glands of obese women. We discuss here preclinical and clinical data suggesting that omega-3 fatty acids (n-3FA) and docosahexaenoic acid (DHA) in particular reduce the risk of obesity-related breast cancer by inhibiting several of the oncogenic pathways activated by obesity. We propose that future clinical trials testing the protective effect of n-3FA against breast cancer should target the subpopulation of obese women using DHA as the n-3FA of choice, possibly in combination with dietary energy restriction or antiestrogens.

2. Obesity and breast cancer

Excess body weight is reaching epidemic proportions with 65% of the adult United States population being either overweight or obese. There is strong evidence that obesity is linked to risk of postmenopausal breast cancer. There are multiple mechanisms by which obesity predisposes to breast cancer such as altering production and bioavailability of critical mitogens such as estradiol [1] and insulin-like growth factor-I (IGF-1) [2]. Insulin resistance associated with obesity can also contribute to mammary carcinogenesis as a result of the high circulating level of insulin acting as a growth factor [3]. Recent interest has focused on the role of adipokines, primarily leptin [4], and adiponectin [5] and inflammatory markers on mammary carcinogenesis [6]. Leptin synthesis and plasma levels increase with obesity and higher leptin levels are associated with an increase in breast cancer [7]. In contrast, adiponectin levels in serum decrease with increased obesity and an inverse association between serum adiponectin levels and breast cancer risk has been reported [8]. In addition, obesity has been shown to create a pro-inflammatory milieu systemically in the visceral and subcutaneous fat and locally in the breast [6]. In breast tissue, saturated fatty acids released from the necrosed adipocytes cause increased production of inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and prostaglandin E2 (PGE₂) by macrophages in response to nuclear factor kappa-light-chain-enhancer of activated B cells activation. These cytokines in turn increase aromatase activity in neighboring adipocytes thus inducing a local hyperestrogenic milieu [9].

3. How can we prevent obesity-related breast cancer?

Prevention of obesity-related breast cancer is challenging. Maintenance of ideal body weight throughout life represents the best approach. However, this is difficult to achieve as indicated by the increasing incidence of obesity not only in Western societies but also developing countries. For the large segment of the population that is already obese, weight loss should be encouraged although it is difficult to maintain on a long-term basis. In addition, it is unclear whether losing excess weight will lower the risk of breast cancer. The best evidence in support of an inverse association between weight loss and cancer comes from bariatric surgery studies, although these have all been observational in design [10]. Moreover, these findings may not be applicable to the obese population at large since they examine the effects of extreme and rapid amounts of weight loss resulting from the procedure. Pharmacologic prevention of breast cancer (including obesity-related breast cancer) with the antiestrogens Tamoxifen and Raloxifene is certainly well established. However, the applicability of these interventions to the population of women at large is limited by their toxicity such as thromboembolic events. Furthermore, a limitation of Tamoxifen and Raloxifene is that neither drug reduces the incidence of estrogen-receptor-negative tumors which are associated with poor prognosis.

Based on preclinical and clinical evidence discussed later, we believe that n-3FA may represent an alternative/complementary approach to prevention of obesity-related breast cancer possibly including estrogen-receptor-negative tumors. We believe that such nutritional intervention would be appealing to the population of women at increased breast cancer risk at large in view of the perceived overall favorable health impact of n-3FA.

4. n-3FA and breast cancer prevention

The contribution of the specific fatty acid composition of the diet to mammary carcinogenesis has received considerable attention in the literature. Among the fatty acids, n-3FA and n-6FA have been suggested to decrease and increase breast cancer risk respectively [11]. Preclinical studies conducted over the last 30 years in a variety of experimental systems of mammary carcinogenesis including estrogen-receptor-negative tumors have been in general supportive of a causal relationship between n-3FA ingestion and reduction of breast cancer development although the results have been variable[12]. Epidemiological studies have been overall inconclusive relative to the protective effect of n-3FA against breast cancer [12]. It is encouraging, however, that a recent meta-analysis of data from 21 independent prospective cohort studies has revealed that dietary intake of marine n-3FA was associated with a 14% reduction in breast cancer risk [13]. Importantly, a dose–response effect was noted with a 5% lower risk of breast cancer per 0.1 g per day increment of n-3FA intake [13].

5. n-3FA reduction of obesity-related breast cancer

In our review of the literature, we identified several key variables that may account for inconsistencies of results regarding the protective effect on n-3FA against breast cancer [12]. Among them is the heterogeneity of the subject populations under investigation with only certain subgroups of women potentially benefiting from n-3FA. Therefore, the degree to which these subgroups are represented could contribute to the variability of the results across studies. We believe that obese subjects may preferentially benefit from the protective effect of n-3FA. From a mechanistic point of view, n-3FA inhibits several of the oncogenic pathways activated by obesity. Specifically, preclinical studies have indicated that n-3FA ameliorate obesity-linked inflammation and insulin resistance [14–16]. Importantly, in a recent study, n-3FA were found to block many of the protumorigenic effects of obesity in a mouse model of postmenopausal breast cancer [17]. In addition, fish oil rich in n-3FA has been shown to increase plasma adiponectin and to decrease plasma leptin concentrations [18], changes which are opposite to those induced by obesity. Furthermore, it has been suggested that a high intake of n-3FA relative to that of n-6FA may decrease endogenous estrogen production via inhibition of aromatase activity/expression which is instead stimulated by excess body weight [18]. The possible preferential protective effect of n-3FA in obese subjects has also been suggested in an epidemiologic study [19].

Support for a preferential protective effect of n-3FA against obesity-related breast cancer is also provided by the results of our recently published clinical trial [20]. In this study, in addition to testing the individual and combined effects of the US FDA-approved formulation of n-3FA, Lovaza (a combination of eicosapentaenoic acid [EPA] and DHA), and the antiestrogen Raloxifene in reducing the breast density, a validated biomarker of breast cancer risk, we tested the hypothesis that body mass index (BMI) influences the relationship between breast density and n-3FA. Using a multivariate regression model, we indeed found a strong negative correlation between absolute breast density and DHA in women with BMI above 29 with a regression coefficient of −4.301 (p-value = 0.0076). In sharp contrast in women with BMI less than 29, the regression coefficient was −0.0080 (p-value = 0.59). This finding suggests that increasing DHA levels will lower breast density and, hence, breast cancer risk only in obese women. Interestingly, no correlation between breast density and EPA was observed in either group. This finding is in agreement with preclinical studies showing a superior antitumor effect of DHA over EPA against breast cancer [21].

6. Future directions

We offer the following suggestions for future studies testing the protective effect of n-3FA in breast cancer.

1. It is likely that not all women will be equally responsive but specific subsets will benefit from the tumor protective effects of n-3FA. We believe that obese women may preferentially benefit, and therefore, we suggest that future studies should target this subgroup, i.e. personalized cancer prevention.

2. We propose that future research should not use fish oil to test the protective effect of n-3FA since the composition of fish oil preparations is heterogeneous and variable from lot to lot. Therefore, research using fish oil is likely to continue giving inconsistent results since the biological actions of the n-3FA present in fish oil are likely to be different and probably tumor specific. To the point, preclinical data [21] and the results of our clinical trial mentioned earlier [20] indicate that DHA (as opposed to EPA) is the most active n-3FA against breast cancer and should preferentially be tested in future trials.

3. Future research should focus on the role of DHA metabolism in mediating its antitumor action. Metabolites of DHA generated through the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways have been shown to have antitumor actions possibly superior to that of DHA itself [22,23]. The production of DHA metabolites is likely to be highly variable among individuals since it is regulated both by genetic and by environmental factors [24]. This can contribute to the variability of the results across studies unless it is taken into careful account.

4. The protective effect of DHA should be tested in conjunction with other interventions with complementary mechanisms of action. For instance, DHA should be tested in conjunction with dietary energy restriction in order to optimize the suppression of oncogenic pathways promoted by obesity. Furthermore, our preclinical data indicates that n-3FA potentiate the antitumor effect of antiestrogens [25]. Although we did not observe any additive/synergistic effect between Lovaza and Raloxifene in our clinical trial with regard to reduction in breast density, these negative results may be explained by the fact that 80% of our subjects were not obese and thus unlikely to benefit from Lovaza administration. Therefore, the potential benefit of the combination of DHA and antiestrogens in reducing breast cancer risk should be tested in future trials targeted on obese subjects.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.