Generally speaking, women with the lowest levels of dietary folate appear to be at increased risk of breast cancer compared to those with high levels, especially in populations that are at risk for folate deficiency. On the other hand, in populations with adequate folate intake, folic acid supplementation appears to increase breast cancer risk, especially in postmenopausal women, although not all studies have found a link. Folic acid supplementation has also been found to promote the progression of established mammary tumors in an animal model of breast cancer. Now a new study has reported a mechanism of action by which folic acid supplementation could reduce the immune system's surveillance and defense against cancer cells.

Folate and folic acid

Folate is a vital water-soluble B vitamin found in a variety of foods, including leafy green vegetables and dry beans. Folic acid is a synthetic form of folate found in supplements and fortified foods. The relationship between folate, folic acid and breast cancer is complex. Population studies have produced contradictory results, in part because, unlike the U.S. and Canada, most countries do not fortify their foods with folic acid. Studies have reported links between dietary folate intake and reduced breast cancer-specific death among women with estrogen receptor negative (ER-) and HER2/neu overexpressing (HER2+) disease.

Sources of folate

We suggest that breast cancer patients and survivors include foods in their diets that incorporate folate rather than taking folic acid. The following foods are good sources of folate, as well as being associated with reduced risk of breast cancer:

Beans, dry
Bell peppers
Brussels sprouts
Cabbage, especially bok choy

Collard greens
Lettuce, romaine
Mustard greens
Summer squash
Turnip greens

Note that both green and black tea reduce intestinal absorption of folate and should not be consumed simultaneously with high-folate foods by those wishing to increase their folate levels.

Sources of folic acid

The U.S. Food and Drug Administration (FDA) requires manufacturers to add folic acid to enriched bread, cereal, flour, cornmeal, pasta, rice, and other processed grain products. Therefore, a "junk food" diet that involves regularly consuming mass-produced breakfast cereal, muffins, donuts, bread, pizza, pasta, hamburgers and other sandwiches, or white rice, could result in relatively high intake of folic acid. Multivitamins also normally contain a substantial level of folic acid.

The Recommended Dietary Allowance (RDA) for folate is 400 mcg DFE for non-pregnant adult women, according to the National Institutes of health. 1 mcg DFE = 1 mcg food folate or 0.6 mcg folic acid from fortified foods or dietary supplements consumed with foods. The Tolerable Upper Intake Level (the level likely to cause adverse health effects) is set at 1,000 mcg per day, which is only 2.5 times the RDA. Note that high intakes of folate from food sources have not been reported to cause adverse effects. It is not clear what level of folic aid intake could affect breast cancer risk or progression. One serving of breakfast cereals contains approximately 100 mcg DFE, or one-quarter of the daily allowance. Folic acid in multivitamins is frequently found at a dose of 400 mcg.

Latest research finds high folic acid reduces natural killer cell activity

The study referenced at the beginning of this news story was designed to investigate the effects of folic acid supplementation on the functioning of natural killer cells in aged mice. Folic acid intake that is higher than the body's capacity to metabolize it results in circulating unmetabolized folic acid. Such unmetabolized folic acid has been found to be associated with reduced ability of natural killer cells to cause the death of targeted cells in postmenopausal women. Natural killer cells are vital for surveillance and defense against cancer cells.

To conduct the study, 16-month-old female mice (at an age well beyond their reproductive life spans) were fed either a standard diet with the recommended dietary allowance of folic acid (control group), or the same diet with 20 times the folic acid RDA (high folic acid group) for three months. Natural killer cell cytotoxicity was then measured in white blood cells harvested from the mouse spleens. Natural killer cell cytotoxicity was found to be significantly lower in splenocytes from mice that had been in the high folic acid group compared to control mice. This appeared to be explained by the significantly lower mature cytotoxic/na´ve natural killer cell ratio found in high folic acid group. Splenocytes from high folic acid mice also produced less interleukin-10 (IL-10) (a protein secreted by immune cells) when stimulated with lipopolysaccharide.

The authors were able to extinguish the difference in natural killer cell cytotoxicity between the two mouse groups by supplementing the splenocytes with IL-10. This suggests that the reduced natural killer cell cytotoxicity caused by high folic acid supplementation was at least partially a result of reduced IL-10 production. The authors conclude that there is a causal relationship between high folic acid intake and reduced natural killer cell cytotoxicity. The study data provides some insights into the potential mechanisms underlying this relationship.