David Cohen, M.D.·Published 6 June 2008·7 min read
Key points
Diets high in fiber have been hypothesized to protect against breast cancer, perhaps due to inhibition of the intestinal reabsorption of estrogens excreted via the biliary system.
Vitamin A Vitamin A consists of preformed vitamin A (retinol, retinyl esters, and related compounds) from animal sources and certain carotenoids found primarily in fruits and vegetables that are partially converted to retinol in the intestinal epithelium (carotenoid vitamin A).
Vitamin E is also an antioxidant and has inhibited mammary tumors in rodents in some, but not all, experiments.
Vitamin C (ascorbic acid) is also an antioxidant and can block the formation of carcinogenic nitrosamines.
Diets high in fiber have been hypothesized to protect against breast cancer, perhaps due to inhibition of the intestinal reabsorption of estrogens excreted via the biliary system. A high-fiber diet has been found to be associated with reduced incidence of mammary cancer in animals. Dietary fiber includes crude fiber that is excreted unchanged and various soluble fiber fractions that may have different biological effects. Epidemiologic assessment of fiber intake has been difficult due to the scarcity of data on the fiber content of individual foods as well as controversy about the most appropriate methods of biochemical analysis to determine fiber content. In a meta-analysis of 10 case control studies in which dietary fiber intake was estimated, a statistically significant relative risk of 0.85 for a 20 g per day increase in dietary fiber was observed. Prospective studies have been less supportive, however. In a Canadian prospective study including 519 cases, a marginally significant inverse association between dietary fiber and breast cancer risk was seen; in another prospective study with a cohort of 344 cases, no suggestion of a protective effect was found. In the Nurses' Health Study, the association between total dietary fiber intake and subsequent breast cancer incidence (1,439 cases) was very close to null, which suggests that any protective effect of dietary fiber is unlikely to be large. The possibility remains, however, that certain subfractions of fiber intake may be relevant to breast cancer causation.
Micronutrients
Vitamin A Vitamin A consists of preformed vitamin A (retinol, retinyl esters, and related compounds) from animal sources and certain carotenoids found primarily in fruits and vegetables that are partially converted to retinol in the intestinal epithelium (carotenoid vitamin A). Many carotenoids are potent antioxidants and thus may provide a cellular defense against reactive oxygen species that damage DNA. Vitamin A is also a regulator of cell differentiation and may prevent the emergence of cells with a malignant phenotype. Retinol inhibits the growth of human breast carcinoma cells in vitro, and retinyl acetate reduces breast cancer incidence in some rodent models.
Human studies of vitamin A intake and breast cancer risk have been mostly case control studies; thus, their interpretation is limited by uncertainty about the extent to which selection and recall bias may have altered the observed estimates of effect. In the earliest and the largest case control study of total vitamin A intake (retinol plus carotenoid vitamin A), a relative risk of 0.8 was seen between women with the highest quartile of vitamin A consumption and the lowest, and a significant inverse trend in risk was noted with increased vitamin A consumption. In a meta-analysis of nine other case control studies with data on vitamin A intake, a significant protective effect of total vitamin A intake on breast cancer was reported. When preformed vitamin A and carotenoids were examined separately, however, the data from these case control studies are more strongly supportive of a protective association for carotenoid vitamin A than for preformed vitamin A. In 1996, specific carotenoids were examined in a case control study that used the USDA-National Cancer Institute carotenoid database. Inverse associations were observed between dietary intake of b-carotene and lutein-zeaxanthin, and risk of breast cancer in premenopausal women.
Written and revised by
David Cohen, M.D.
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The limited available prospective data suggest a possible modest inverse association between vitamin A intake and breast cancer. In two cohorts with 123 and 344 cases of breast cancer, a weak inverse association or no association was observed. In a cohort of Canadian women (519 cases), a marginally significant protective association between total vitamin A intake and breast cancer was seen, with both preformed vitamin A and b-carotene contributing to the inverse association. In the 8-year analysis of the Nurses' Health Study, which included 1,439 cases, a modest (relative risk, 0.8) but significant protective association for total vitamin A was apparent. At 14 years of follow-up (2,697 cases), the inverse association with total vitamin A intake was limited to premenopausal women. This inverse association was accounted for primarily by carotenoid sources of vitamin A; when specific carotenoids were examined, intake of b-carotene and lutein-zeaxanthin were found to be associated with reduced risk, but intake of lycopene was not. The inverse associations with specific carotenoids were strongest among women with a family history of breast cancer.
An alternative to the dietary assessment of vitamin A intake is the measurement of vitamin A compounds in blood. Most studies have assessed blood retinol, however, which is uninformative about vitamin A intake in well-nourished populations, because the liver maintains relatively constant blood retinol concentrations. Blood levels of b-carotene do reflect b-carotene intake, however. Unfortunately, little consistency is seen among the studies examining this compound, probably related in part to their small size.
Thus, available data are suggestive, but not conclusive, of a modest protective association between vitamin A intake and breast cancer. The evidence is stronger for benefits of carotenoid sources of vitamin A. Also, evidence of benefit is stronger for premenopausal women. Other anticarcinogens in vegetables and fruits, including carotenoids such as lutein, may be responsible for the apparent benefits. The effect of vitamin A supplements, either in the form of preformed vitamin A or carotenoids, should be evaluated in randomized trials. A randomized trial of fenretinide, a powerful synthetic retinoid, in the prevention of contralateral breast cancer in women already diagnosed with a first breast cancer is under way in Italy. The Women's Health Study of 40,000 female health professionals is a randomized trial designed to test whether b-carotene or vitamin E supplements reduces breast cancer risk. The b-carotene arm was terminated in 1996, however, after reports from trials in Finland and the United States that b-carotene supplements appeared to increase the risk of lung cancer among smoking men. Thus, data from randomized trials on specific carotenoids and breast cancer risk, particularly among premenopausal women, may never be available.
Vitamin E
Vitamin E is also an antioxidant and has inhibited mammary tumors in rodents in some, but not all, experiments. Relatively few studies are available to assess the association between dietary vitamin E intake and breast cancer, and none of the published prospective studies has reported a significant inverse association. In the largest of these, no evidence of a protective effect was seen with use of vitamin E supplements, even at high doses for long duration.{pagebreak}
Vitamin C
Vitamin C (ascorbic acid) is also an antioxidant and can block the formation of carcinogenic nitrosamines. Few animal studies have assessed the effect of vitamin C on mammary cancer; in a study in rats, ascorbic acid had no effect on the growth of either transplanted or dimethylbenzanthracene-induced mammary tumors.
In the largest case control study reported, no effect for vitamin C was observed; however, in a subsequent study by the same group, a significant protective effect was present (relative risk of 0.6 for highest versus lowest quartile). In a meta-analysis of nine other case control studies with data on vitamin C, a significant inverse association (relative risk of 0.7 for each 300 mg per day increase in vitamin C) was observed.
In prospective studies, however, no significant association between intake of vitamin C and breast cancer was observed. In the 14-year follow-up of the Nurses' Health Study, no evidence of any reduction in risk was seen with long-term use of vitamin C supplements. Thus, the existing data on intake of vitamin C and breast cancer risk are somewhat inconsistent. However, the available prospective data do not support benefits of high vitamin C intake for reducing breast cancer risk.
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Selenium
Selenium is an important component of the antioxidant enzyme glutathione peroxidase, inhibits cell proliferation, and, in animal studies, has been shown to protect against a variety of cancers, although usually at high levels of intake. In the United States, ecological studies have shown strong inverse associations between county-specific and national measures of selenium exposure and breast cancer rates.
Selenium intake cannot be measured accurately by means of dietary assessment in geographically dispersed populations, because the selenium content of individual foods varies greatly depending on the geographic area in which the foods were grown. Selenium levels in tissues such as blood and toenails do reflect selenium intake, however, and thus provide an informative measure of diet.
Several studies using these biomarkers of selenium intake have been performed. In one relatively small study, a nonsignificant positive association was observed between erythrocyte selenium level and breast cancer. In the largest prospective study, Hunter et al. observed no association between selenium levels in toenail and risk of breast cancer during 4 years of follow-up.
Of the other prospective studies, only the study of Knekt et al. from Finland showed any evidence of an increased risk among women in the lowest category of selenium level. As women in Finland at that time had extremely low selenium intakes, this observation is consistent with the possibility that a threshold exists below which low selenium intake does increase breast cancer risk. In a small randomized trial, breast cancer was the only malignancy that occurred more frequently among those receiving selenium supplements. Taken together, these data suggest that increases in selenium intake are unlikely to reduce risk of breast cancer for most women in countries with existing moderate or high levels of selenium intake.
Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz
W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts B. Rockhill: Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts
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