In animal studies, omega-6 PUFAs have a strong mammary tumor-enhancing effect [21
]. In order to exert their carcinogenic effects, they must first undergo an oxidative metabolization, mainly through the lipoxygenase and cyclooxygenase pathways [23
]. The main substrate of these oxidative pathways is arachidonic acid, which is mainly produced from dietary linoleic acid, the most common omega-6 PUFAs in Western foods and cooking fats. Several recent epidemiologic studies have found a positive association between dietary omega-6 PUFAs and breast cancer risk [25
]. Certain analyses took into account a genetic predisposition related to omega-6 metabolism. To determine whether 5-lipoxygenase (LOX)-mediated dietary omega-6 metabolism might influence breast cancer risk, investigators examined genetic variants of the LOX enzyme in combination with linoleic acid intakes [25
]. They found that women with a genetic aberration affecting the LOX enzyme whose diet provided a high level of omega-6 (linoleic acid) had a significantly increased breast cancer risk [25
]. However, when women with the same high-risk genetic profile had a diet lower in linoleic acid, their genotype had no significant effect on their breast cancer risk. This demonstration that a diet-gene interaction increases the risk of cancer may explain why some previous studies were inconsistent or conflicting. Other recent studies have shown interactions between heterocyclic amines and omega-6 PUFAs on the one hand [26
], and between omega-3 and omega-6 on the other hand [27
], in determining the risk of invasive breast cancer. Other factors, such as the obesity status [28
], were shown to affect the association between dietary PUFAs and breast cancer risk. Finally, the food sources of omega-3 and omega-6 PUFAs, as well as their relative amounts in the diet of individuals, appear to be very important for breast cancer risk [29
Thus, there are several recent and concordant studies that strongly suggest that dietary omega-6 PUFAs - the consumption of which is encouraged worldwide to decrease blood cholesterol - increase the risk of breast cancers. In the same line of reasoning, it is important to recall that the most frequently prescribed cholesterol-lowering drugs (including statins) increase the blood concentration of arachidonic acid, the main omega-6 PUFA in cell membranes [31
]. Also, studies have suggested that low cholesterol and/or cholesterol-lowering are associated with an increased risk of cancers [32
]. Thus, despite the fact that many confounders tend to obscure the effects of cholesterol-lowering drugs on the clinical occurrence of cancers, the association of high intake of omega-6 and statins - both aimed at reducing blood cholesterol to prevent CVD - may add up to increase cancer risk, in particular breast cancer risk. Further studies are urgently needed to explore the issue.
It could be said that most data regarding the effects of dietary omega-6 PUFAs on cancers are observational [25
] and do not demonstrate cause-effect relationship. Only randomized trials can demonstrate causality. In fact, two dietary trials not initially designed to test a diet-cancer hypothesis, the Veterans Los Angeles trial [33
] and the Lyon Diet Heart Study [34
], provided some information about dietary omega-6 and cancers. In the Los Angeles trial, there was a huge increase in dietary omega-6 in the experimental group compared with the control group (15% total energy versus 5%) and there was a significant increase in the incidence of new cancers and in cancer mortality in the high omega-6 group [33
]. By contrast, in the Lyon trial, the intake of omega-6 was slightly but significantly reduced in the experimental group (3.6% total energy versus 5.3%) and there was a significant decrease in cancer incidence in the low omega-6 group [34
]. These two trials with very different amounts of omega-6 in the experimental groups do not definitely demonstrate that omega-6 fatty acids per se increase the risk of cancer - other dietary factors and various interactions (including drug treatment as mentioned above) likely played a role in the clinical surfacing of new cancers and their severity - but they clearly signal that lipid profiles with high or relatively high (> 5% energy) omega-6 tend to increase the risk of cancers, which is in line with the observational studies discussed above.
At the same time, omega-3 PUFAs were shown to have chemopreventive properties against various cancers and their complications, including colon and breast cancer [35
]. It is therefore important to design dietary strategies that will result in increased omega-3 in diet, blood and tissues, associated with decreased omega-6. In addition to increasing the dietary intake of omega-3, it is possible to stimulate the endogenous synthesis of very long-chain omega-3 PUFAS - often called 'marine' omega-3 - out of their plant substrate alpha-linolenic acid, through the consumption of plant pigments such as the polyphenols found, for instance, in grapes and red wine [37
]. Both alpha-linolenic acid and the polyphenol anthocyanins are present in quite large amounts in the traditional Mediterranean diet, also poor in omega-6, which may at least partly explain the remarkable protection this diet provides against cancers [40
]. In contrast, the main dietary omega-6 linoleic acid inhibits synthesis and cell incorporation of long-chain omega-3 PUFAs [42
] which is in line with the effects of omega-6 on cancer risk as discussed above.
The association of oleic acid - the main fatty acid of olive oil, a major component of the Mediterranean diet - with breast cancer risk has been analyzed in several studies [44
] and provided conflicting data. In fact, it is only when the level of oleic acid in blood or cells was used in the analyses (and not as a nutrient through a frequency questionnaire) that it was positively associated with cancer risk [46
]. The level of oleic acid in blood and tissue is more dependent on endogenous metabolism than on dietary intake. The main enzymatic system regulating oleic acid level is the delta-9 desaturase - also called stearoyl-coenzyme A desaturase - and its activity depends on dietary (carbohydrate intake), hormonal (insulin) and lifestyle (physical exercise) factors [47
]. Thus, blood concentration of oleic acid is not a surrogate of the consumption of oleic acid but rather a biomarker of lifestyle associated with insulin resistance, which is by itself positively associated with the risk of breast cancer [48
]. Finally, dietary oleic acid is not necessarily a marker of olive oil consumption as it is also one of the main fatty acids of meat. It is critical in epidemiologic studies analyzing the relationships between oleic acid intake and any clinical outcome to include the geographic area of the studied population: in the Mediterranean area, the dietary source of oleic acid is mainly olive oil (a plant food) whereas in most Western countries, animal foods are the main sources of oleic acid. Importantly, olive oils contain more than the sole lipids; certain phytonutrients such as polyphenols may also interfere with the risk of cancers [49
]. Thus, when analyzing the relationships between breast cancer and dietary habits, the type of fatty foods - plant versus animal - is as important as the type of fatty acids.