Environmental factors, including those related to diet, are believed to contribute significantly to the cause of many forms of cancer. Dietary fat intake is among the most widely studied dietary risk factors for breast and prostate cancers.

In recent years, increasing attention has been paid to the intake of specific fats rather than total fat intake, and notable among these have been fish oils. Long-chain EPA and DHA, which are polyunsaturated omega-3 fats contained primarily in fatty fish, have been shown consistently to inhibit the proliferation of breast and prostate cancer cell lines in the test tube and to reduce the risk and progression of these tumors in animal experiments.

Regarding fish consumption, the concentrations of EPA and DHA in fish oil vary between fish species, with relatively high concentrations found in fatty species native to cold waters, such as salmon, mackerel, sardines, and herring, and relatively low concentrations in lean fish, such as sole, halibut, and cod. The interpretation of "total fish consumption" in epidemiologic studies can therefore be problematic, because the absolute and relative amounts of fatty acids reflected in this measure vary greatly among populations.

Many studies examined fish consumption in relation to breast and prostate cancer risk, although only a few accounted for the type of fish consumed or examined the intake of specific marine fatty acids. The studies also varied greatly with respect to important methodologic factors, such as sample size, adjustment for potentially confounding variables, the detail and quality of the dietary assessment, and the duration of follow-up.

In addition, epidemiologic studies to date have not examined intakes of specific fat in relation to endometrial and ovarian cancers. Clinical and experimental studies of these cancers also have been scarce.

How Fish Oil Prevents Cancer

Several mechanisms have been proposed by which the intake of marine fats may lower the risk of cancer. Among the most important of these is the inhibition of eicosanoid biosynthesis from arachidonic acid (AA; 20:4n-6), an omega-6 fat metabolized in the body from linoleic acid. Eicosanoids are a class of compounds derived from polyunsaturated acids and include prostaglandins, hydroxyeicosatetraenoic acids, and leukotrienes.

Prostaglandins are oxygenated, unsaturated cyclic fats that perform a variety of hormone-like actions. Those converted from AA by the cyclooxygenase-2 enzyme, notably prostaglandin E2 (PGE2), have been linked to carcinogenesis in several types of studies:

• Animal experiments of mammary tumor development,
• Studies of the proliferation of breast and prostate cancer cell lines in vitro, and
• Human studies of fish oil intake, epithelial cell proliferation rates, and PGE2 biosynthesis.
  

Tumor cells typically produce large amounts of AA-derived PGE2, which may impede immune system function, possibly through its role in the generation of suppressor T cells. Fish oils inhibit cyclooxygenase-2 and the oxidative metabolism of AA to PGE2.

EPA and DHA also have been shown to inhibit lipoxygenase which metabolizes AA to hydroxyeicosatetraenoic acids and leukotrienes. Hydroxyeicosatetraenoic acid has been linked to the suppression of apoptosis, the stimulation of angiogenesis, stimulation of tumor cell adhesion, and expression of the invasive phenotype.

Lipoxygenase inhibitors have also been discussed recently as a potentially important class of chemopreventive agents.

Eiocosanoids derived from AA also may be involved in other processes related to cancer progression, as well as cancer initiation. These include:

• Alteration of tumor cell membranes
• Modulation of oncogene expression
• Formation of cytotoxic peroxidation products
• Inhibition of mitosis
• Promotion of insulin resistance
• Modification of estrogen metabolism
  

Estrogen can be metabolized along 2 major pathways, to 16-{alpha}-hydroxyestrone or to 2-hydroxyestrone. 16-{alpha}-Hydroxyestrone is considered to be the more biologically active of the 2 estrogen metabolites and has been observed to increase mammary epithelial cell proliferation rates in experimental studies.

In contrast, 2-hydroxyestrone may decrease proliferation and has been associated in some, but not all, studies with reduced breast cancer risk. Thus, "Western" diets that are rich in linoleic acid may decrease the production ratio of 2-hydroxyestrone to 16-{alpha}-hydroxyestrone and thereby increase cancer risk.

Several studies focused specifically on DHA and its role in the development of breast and prostate cancers. For example, DHA may activate peroxisome-proliferator activated receptor-{gamma}, ligands of which have shown antiproliferative effects in vitro on prostate cancer cell lines. DHA also has been shown to improve the response of breast tumors to cytotoxic agents.

Differences in Fish Oil Consumption

Studies of fish oil consumption trends have shown inverse associations between per capita consumption of fish oil and the incidence of and mortality rates from prostate and breast cancer. Moreover, the shift toward a Western diet usually involves a concurrent decrease in omega-3 fat intake and increase in omega-6 fat intake, such as that observed in Japan over the past several decades (with a concurrent rise in breast cancer incidence).

Whereas the intakes of these two classes of fats were, for most of human history, similar in quantity (i.e., an intake ratio near unity), modern diets now heavily favor the intake of omega-6 fats. Indeed, the results of several human and animal studies suggest that reductions in breast cancer and PGE2 biosynthesis can best be achieved with a relatively high intake ratio of omega-3 to omega-6 fats.

Hence, the processes that ultimately modulate the concentration of tumor growth–enhancing eicosanoids may depend more on the relative concentrations of specific fatty acids in the diet than on their absolute concentrations.

The concentrations of EPA and DHA relative to those of other fats contained in fish vary between species, and relatively high concentrations are found in fatty fish, such as salmon, mackerel, sardines, and herring, species that are generally native to cold waters. Lean fish, which typically are native to warmer waters, tend to have lower concentrations of EPA and DHA and may sometimes have higher concentrations of AA.

For example, a 100-g serving of Pacific herring contains 1.0 g EPA and 0.7 g DHA (19). In contrast, a 100-g serving of haddock contains 0.1 g each of EPA and DHA. Thus, different types of fish may have different effects on processes related to cancer development.

Factors Complicating Proper Interpretation of Fish Oil Clinical Studies

For studies that examined only total fish consumption in relation to cancer risk, assumptions regarding the type of fish consumed (and, therefore, EPA and DHA intake) can be made from the per capita intake of fish oil. For example, total fish consumption in a Scandinavian population might reflect a greater intake of fatty fish than would the same total fish consumption in a population in the United States, because the per capita intake of omega-3 fats and the per capita intake ratio of omega-3 to omega-6 fats in Scandinavia are up to 5- and 10-fold, respectively, those in the United States.

Data from a few experimental studies suggest that the strength of the association with fish oils may be reduced in the presence of high antioxidant intake, because both the former and the latter inhibit the formation of AA-derived peroxidation products. This has been put forth as a potential reason for the largely negative results of studies in the United States, where supplementation with antioxidants is widespread.

However, this explanation is not entirely convincing because the formation of cytotoxic peroxidation products is only one of several mechanisms that may underlie the association between fish oils and cancer risk. Nevertheless, adjustment for dietary antioxidants in ecologic and analytic studies of omega-3 fatty acids to date has been infrequent.

Intake of fish oils also has been observed to inhibit the metastasis of human breast cancer cell lines growing as solid tumors in animal models. Hence, the association between fatty acids and cancer risk may be clarified further through the analysis of epidemiologic data that take into account various follow-up (or induction) periods, that are from studies with repeated assessment of diet during the follow-up period, and that provide information on cancer at various stages of growth and progression.

In conclusion, the development and progression of breast and prostate cancers appear to be affected by processes in which EPA and DHA play important roles.

Given the lack of studies that examined the intake or tissue concentrations of specific fish oils and the fact that most studies of fish consumption did not account for the type of fish consumed, there are still too few data from epidemiologic studies to evaluate the strength, consistency and dose response of the relation between fish oil intake and human cancer.

Although there is ample evidence from test tube and animal studies that these essential fats can inhibit the progression of tumors in various organs, particularly the breast and prostate, the evidence from epidemiologic studies is less clear. Although most of the studies did not shown an association between fish consumption or fish oil intake and the risk of hormone-related cancers, the results of the few studies from populations with a generally high intake of fish oils are encouraging.

American Journal of Clinical Nutrition, Vol. 77, No. 3, 532-543, March 2003

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