© The Author 2006. Published by Oxford University Press.
ARTICLE |
Meta-analyses of Observational and Genetic Association Studies of Folate Intakes or Levels and Breast Cancer Risk
Affiliation of authors: Department of Social Medicine, University of Bristol, Bristol, U.K.
Correspondence to: Sarah J. Lewis, PhD, Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, U.K. (e-mail: s.j.lewis{at}bristol.ac.uk).
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ABSTRACT |
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Background: Evidence from case–control studies suggests that increasing dietary folate intake is associated with a reduced risk of breast cancer. However, large cohort studies have found no such association, and animal studies suggest that folate supplementation may promote tumorigenesis. We conducted a meta-analysis to summarize the available evidence from observational studies on this issue and a meta-analysis of the association between a common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate metabolism, and breast cancer risk. Methods: We searched Medline and ISI Web of Knowledge databases for relevant studies that were published through May 31, 2006. We used random-effects analysis to calculate odds ratios (ORs) for case–control studies or relative risks (RRs) for cohort studies for a 100-µg/d increase in folate intake. Unadjusted odds ratios were calculated for the studies of MTHFR genotype based on published genotype frequencies. Results: A total of 13 case–control studies and nine cohort studies were included in the meta-analysis of folate intake and breast cancer risk. We found a summary OR of 0.91 (95% confidence interval [CI] = 0.87 to 0.96) from the case–control studies and a summary RR of 0.99 (95% CI = 0.98 to 1.01) from the cohort studies for a 100-µg/d increase in folate intake. We found evidence that the case–control studies may have suffered from substantial publication bias. The case–control and cohort studies may have been subject to measurement error, confounding, and possibly spurious associations arising from subgroup analyses; in addition, the case–control studies were potentially subject to recall bias and publication bias. Seventeen studies were included in the meta-analysis of MTHFR C677T genotype and breast cancer risk. We found no difference in breast cancer risk between MTHFR 677 TT homozygotes and CC homozygotes (OR = 1.05, 95% CI = 0.88 to 1.25), and there was no evidence of an interaction between folate intake and MTHFR genotype on breast cancer risk. Conclusion: A lack of dietary folate intake is not associated with the risk of breast cancer.
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INTRODUCTION |
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Folate is important for purine synthesis and DNA methylation, two key processes responsible for maintaining DNA integrity and regulating gene expression. Folate deficiency has been associated with uracil misincorporation, increased susceptibility of DNA to strand breaks, aberrations in DNA methylation, and disruption of DNA repair (1–3). Because all these mechanisms are important in carcinogenesis, it is possible that folate intake is associated with the development of breast and other cancers.
Several reviews have highlighted the importance of adequate folate intake in breast cancer prevention (4–7). If folates were found to have a role in breast cancer prevention, it could easily be given to reduce risk because health advice aimed at increasing folate intake or fortification of food would be easy to implement. Recommendations to increase folate intake by pregnant women to reduce neural tube defects have been successful. However, misinformation regarding folate intake and breast cancer risk could be detrimental, either directly if consumption of high levels of folate is harmful, or indirectly, if high quantities of folate are consumed to compensate for other lifestyle factors that may increase the risk of breast cancer.
Analyses of genotypes associated with folate metabolism can be used as a tool to determine whether the folate metabolic pathway is important in disease. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which acts as a methyl donor for homocysteine remethylation to methionine, which is required for nucleic acid methylation (1). Folate that is not converted via this pathway enters another pathway that leads to purine synthesis, a process that is important in DNA repair. A common genetic variant in the MTHFR gene has been identified in which a C to T substitution at nucleotide position 677 (C677T) results in an alanine to valine substitution and the production of a thermolabile variant of the MTHFR enzyme that has approximately 30% of the activity of the wild-type enzyme (8,9). Individuals who are homozygous for the T allele have lower levels of DNA methylation and higher levels of formylated tetrahydrofolates in red blood cells than CC homozygotes (10). If low dietary folate intake were associated with an increased risk of breast cancer, then the MTHFR C677T polymorphism should also be associated with an increased risk of breast cancer, although this association could be modified by folate intake. That is, there could be an interaction between folate and the MTHFR genotype, such that individuals with the TT genotype might be at increased risk of breast cancer at low levels of dietary folate because the MTHFR enzyme they produce is less active and so less folate is made available for DNA methylation. By contrast, in folate-replete conditions, the TT genotype might provide an advantage over the CC genotype because a less active enzyme would mean that more 5,10-methylenetetrahydrofolate would be available for nucleotide synthesis.
Investigations of associations between genetic variants that modify levels of an exposure of interest and disease can be used to make inferences about the relationship between an exposure and a disease (11,12). We carried out a systematic review and meta-analysis of observational studies that examined associations between folate intake and breast cancer risk to clarify whether the reported associations arising from observational studies are real or have arisen as the result of a combination of chance, bias, measurement error, inappropriate subgroup analysis, or confounding. We also carried out a systematic review and meta-analysis of the association between the MTHFR C677T polymorphism and breast cancer risk.
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METHODS |
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Search Strategy
We searched the Medline and ISI Web of Knowledge databases for studies on folate intake or biomarkers of folate levels and breast cancer and on the MTHFR C677T polymorphism and breast cancer that were published through May 31, 2006. The following search algorithm was used for the review on folate intake or level and breast cancer: (breast) AND (cancer OR malignancy OR tumour OR tumor) AND (folate OR folic acid). The following search algorithm was used for the review on MTHFR polymorphism and breast cancer: (breast) AND (cancer OR malignancy OR tumour OR tumor) AND (MTHFR OR methylenetetrahydrofolate reductase). Publications were also identified by reviewing the bibliographies of retrieved articles. No studies were excluded on the basis of language; non–English language publications were translated into English. When multiple publications reported on the same population, we used the most recent publication only. For studies that did not provide raw data or give point estimates (odds ratios [ORs] or relative risks [RRs]) in the initial publication, we attempted to obtain this information by correspondence with the authors. When such information could not be obtained, the studies were excluded.
Data Extraction
We followed a standard protocol for data extraction. For each study, the following data were recorded: first author's name, year of publication, country in which the study was performed, name of the study (if given), study design, number of case and control subjects, source of the control subjects, whether women in the study were pre- or postmenopausal, method of assessment of folate levels, categories of folate intake or serum folate levels, covariates for adjustments in multivariable models, effect estimates (i.e., relative risks or odds ratios) and 95% confidence intervals (CIs) for dietary folate intake or serum folate levels and breast cancer risk, effect estimates and 95% confidence intervals for dietary folate intake plus supplement intake and beast cancer risk, effect estimates by menopausal status, effect estimates for alcohol and folate interactions (including the cut points used for alcohol and folate intakes), and results of trend tests. For the genotype studies, we extracted all the above information, when available, plus data on the distribution of genotypes among the case and control subjects, the effect estimates for MTHFR C677T genotype and breast cancer risk, and the effect estimates for interactions between genotype and dietary folate intake or serum folate level, including cut points.
Statistical Analysis
Published odds ratios and relative risks are presented for the observational studies of folate intake and breast cancer in Table 1. To make comparisons across studies, we calculated the odds ratios for case–control studies or relative risks for cohort studies for a 100-µg/d increase in folate intake by using either continuous odds ratios (or relative risks) or odds ratios (or relative risks) across categories of folate intake for each study. For these comparisons, we considered dietary folate intake only because this variable was reported by all studies, whereas folate intake from both diet and from supplement use was not. We did not include studies of biomarkers of folate. When data were presented according to quantiles or other categories of exposure, we used the median or mean exposure in each group when they were reported. When the median or mean exposures were not reported (as was the case for the majority of reports included in the meta-analyses), we estimated the mean exposure in each group based on the distribution of exposures among subjects across groups, as described by Chene and Thompson (13). This method addresses the problem of unbounded upper and/or lower categories by assuming a normal distribution of the exposure in the population. When the number of individuals in each quantile was not reported, we assumed that the quantile groups were of equal size.
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When the number of individuals in each group was presented in the paper but no odds ratios or relative risks were given, the unadjusted log odds ratio or relative risk per 100-µg/d increase in folate intake was estimated directly using logistic regression. When either unadjusted or adjusted odds ratios or relative risks comparing quantiles or groups were presented, these were used to calculate odds ratios or relative risks for a 100-µg/d increase in folate intake as follows: If no confidence intervals, standard errors, or P values were reported, we estimated the standard error of the log odds ratio (or relative risk) from the number of subjects with and without disease in each group using the formula described by Woolf (14). We then estimated the log odds ratio (or relative risk) per 100-µg/d increase in folate intake using the method of Greenland and Longnecker (15). This method accounts for the correlations between estimates of odds ratios/relative risks for different folate levels that have been compared with the same reference level and preserves adjustments for confounders in the reported odds ratios and relative risks. We performed one subgroup analysis of menopausal status at diagnosis of breast cancer.
We used published genotype frequencies to calculate unadjusted odds ratios for the studies of MTHFR genotype associations. For one study, which was stratified by ethnic group, a different effect estimate was used for each group. In the analyses of all studies, random-effects meta-analysis was used to calculate summary odds ratio estimates. Each summary estimate was a weighted average of the estimates from each study, where the weight for each study is the inverse of the sum of the within-study variance for that study and the between-study variance, which was estimated by the method of moments (16). All statistical analyses were carried out with the use of Stata statistical software (version 9; Stata Corporation, College Station, TX). All statistical tests were two-sided.
We assessed small-study effects, including publication bias, for studies of dietary folate intake and of the MTHFR polymorphism by computing both the Egger (17) and Begg (18) tests. To assess whether there was an interaction between MTHFR genotype and folate intake, we extracted or calculated the odds ratio for TT versus CC genotype in high and in low folate conditions separately, where possible.
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RESULTS |
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Meta-analysis of Observational Studies of Folate Levels and Breast Cancer Risk
We identified 14 case–control (19–32) and 11 cohort studies (33–44) that examined the association between breast cancer risk and folate levels, as determined by completion of a dietary intake questionnaire or by measuring biomarkers of folate; one cohort study reported associations of both folate intake and serum folate with breast cancer risk (33,42) (Table 1). Of these studies, eight case–control studies (19,20,24–26,28,31,32) and no cohort studies found evidence at the conventional level of statistical significance (P<.05) of an association between folate intake and breast cancer risk. Meta-analysis of the 13 case–control studies (19–30,32) and nine cohort studies (33–40,44) that measured folate intake rather than biomarkers of folate found a summary OR of 0.91 (95% CI = 0.87 to 0.96) for the case–control studies and a summary RR of 0.99 (95% CI = 0.98 to 1.01) for cohort studies for a 100-µg/d increase in folate intake (Fig. 1). There was strong heterogeneity between study types (P<.001). When the analysis was restricted to premenopausal breast cancer, the summary OR for case–control studies was 0.87 (95% CI = 0.78 to 0.97) and the summary RR for the cohort studies was 1.01 (95% CI = 0.98 to 1.04) (Fig. 2), again with strong evidence of heterogeneity by study type (P = .001).
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Separate application of the Egger test (17) to the case–control and cohort studies showed that the effect estimates were related to study size in the case–control studies (P values for the Egger test = .01 [case–control studies] and .08 [cohort studies]). Thus, small-study effects, such as publication bias, may have resulted in an exaggerated effect estimate for the case–control studies but not for the cohort studies.
Folate Supplementation
Two case–control studies (29,30) presented raw data on folate intake from supplements only for case and control subjects. The summary OR for the association of folate supplementation compared with no folate supplementation with breast cancer risk from these studies was 0.97 (95% CI = 0.85 to 1.11). Three cohort studies (35,40,44) reported either raw data or a relative risk for women who took folate supplements compared with those who did not; the summary RR for supplementation from these three studies was 1.00 (95% CI = 0.86 to 1.17). Other studies (22,36,41,42) found no association between breast cancer risk and multivitamin use, but these studies did not report specifically on folate supplementation.
Interaction With Alcohol Intake
Seven cohort studies (33–36,39,40,44) and one case–control study (24) examined the interaction between alcohol and folate intakes with respect to breast cancer risk (Table 2). Only one of the reported P values (33) suggested strong statistical evidence of an interaction between folate and alcohol intake (Table 2). Only two studies used the same cut points for alcohol intake (33,34). Therefore, evidence for an interaction between folate and alcohol is inconclusive.
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Meta-analysis of the MTHFR C677T Polymorphism and Breast Cancer Risk
A meta-analysis of 17 studies (27,30,38,45–58) of the MTHFR C677T polymorphism and breast cancer risk included a total of 6373 case subjects and 8434 control subjects (Table 3). The summary odds ratio for TT homozygotes versus CC homozygotes was 1.04 (95% CI = 0.94 to 1.16) (Fig. 3, A). In addition, we found that the summary odds ratio for heterozygotes versus TT and CC homozygotes considered together was 1.01 (95% CI = 0.94 to 1.08) (Fig 3, B). This analysis was done because it has been proposed that MTHFR C677T TT genotype either increases or decreases the risk of cancer depending on circulating folate levels (59); if this were the case, one would predict that heterozygotes would have a lower risk of breast cancer than either homozygote. One small study [n = 149; (60)] of the association between MTHFR C677TT genotype and breast cancer, which was not included in our meta-analysis because it was published as an abstract only and we did not have access to the raw data or an odds ratio, reported a higher frequency of the T allele among case subjects that was of borderline statistical significance (P = .04). Genotypes showed no strong evidence of deviating from Hardy–Weinberg equilibrium in all control populations. The Egger test revealed no strong evidence that effect estimates were related to study size (P = .36).
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Four studies (27,30,38,54) examined the interaction between MTHFR genotype and dietary folate intake (Table 4). Two of these studies (30,54) showed a greater increase in breast cancer risk associated with the TT genotype at low folate levels than at high folate levels, although results were not statistically significant at the conventional P<.05 level. Another two studies showed no strong evidence of an interaction (27,38). Beiby et al. (31) also examined whether there was an interaction between serum folate levels and MTHFR C677T genotype and found no strong evidence of an interaction; however, that study lacked statistical power to detect such an interaction.
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DISCUSSION |
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We found no consistent or reliable evidence from the cohort studies included in our systematic review of an association between dietary folate intake and the risk of breast cancer, whereas the case–control studies showed a risk reduction associated with dietary folate intake. We found no evidence of an association between the MTHFR C677T polymorphism and breast cancer risk. Randomized controlled trials (61,62) have provided no evidence of an association between folate intake and breast cancer risk. In a 36-year follow-up study of a trial in which women were randomly assigned to take either 200 µg or 5 mg folate per day or a placebo during pregnancy, Charles et al. (61) found that women in the high folate supplementation group had twice the risk of death attributable to breast cancer compared with women in the placebo group. However, the number of deaths was small and the 95% confidence intervals for the hazard ratios for breast cancer mortality were wide, suggesting that these results may be due to chance; nevertheless, these findings also do not support an association between folate intake and reduced breast cancer risk. Another randomized controlled trial, which was carried out in myocardial infarction survivors, the Norwegian Vitamin Trial (62), found a relative risk for cancer death of 1.4 (P = .08) among those supplemented with folic acid compared with the control group. However, that trial did not specifically report the numbers of breast cancer deaths among the groups or the effect of supplementation on breast cancer.
The purpose of this systematic review was to assess whether there is evidence based on observational evidence that there is an association between folate intake and breast cancer risk. Our study, like all meta-analyses, has limitations that are based largely on the availability and quality of the published data. Our goal was to include all published epidemiologic studies on folate and breast cancer. However, we found evidence—particularly among the case–control studies—that small studies showed larger effect sizes, which suggests publication bias. Preferential publication of positive studies would lead to an overestimation of the association between folate intake and breast cancer risk in this meta-analysis, particularly among the case–control studies. In addition, recall bias may explain why an association has arisen in case–control studies but not in cohort studies.
The association between breast cancer risk and folate intake that was seen in the case–control studies may be real or it may be due to a combination of chance, measurement error, bias, and confounding. In addition, the association reported previously between folate intake and breast cancer risk among alcohol drinkers (33) may be due to overemphasis of results from subgroup analyses.
In dietary studies of many nutrients, apparently statistically significant associations will arise by chance. Chance findings coupled with publication bias observed in case–control studies could account for the case–control odds ratio (63).
There are several problems inherent in measuring folate intake. The majority of studies included in our meta-analysis determined folate intake by use of food frequency questionnaires, which are subject to substantial measurement error (64). The measurement error is the result of a combination of misreporting of food intake by study subjects, imprecisely worded questions about food intake, and measurement error in the tool that is used to convert food intake into nutrient levels. Indeed, a recent editorial (65) questioned whether it was time to abandon the food frequency questionnaire. Because nutrient levels in a particular food item may vary by factors related to its growth or production, such as the season, the composition of the soil, and the climate, as well as the cooking method, conversion of food items into nutrient levels is also likely to be inaccurate. Measurement of dietary intake at a single time point may also not be a good indicator of a person's average lifetime exposure to a particular nutrient. Hao et al. (66) measured folate levels in plasma and in red blood cells from 2422 adults in China and found seasonal variations in folate levels that were consistent with the seasonal availability of vegetables that have a high folate content. Validation of the dietary questionnaire used in the Nurses' Health Study found that the ratios of within- to between-person variance for 55 food items computed using four 1-week dietary records were, in general, greater than 1.0 and as high as 14.8 for spinach, which has a high folate content (33,67). In one of the studies on breast cancer risk and folate intake (26), the intraclass correlation coefficient for folate intake measured on two occasions was 0.36 (26,68). In another study, the intraclass correlation coefficient for folate measured by food frequency questionnaire compared with a 24-hour recall was 0.26 (35).
Measurement error can also arise from changes in folate consumption. Many of the studies included in this review recruited subjects over a period of several years from the mid to late 1990s. Folate concentrations in food were changing rapidly during this period because folate fortification of cereals became compulsory in the United States and Canada by the end of 1997. This change in folate consumption over time is likely to have resulted in increased misclassification of the folate content of food in some of these studies.
All the forms of measurement error described above are nondifferential and therefore likely to lead to an underestimation of effects. By contrast, selection and recall bias, subgroup analyses, and confounding are likely to overestimate the association between folate intake and breast cancer risk.
The potential problems of selection, response, and recall bias in case–control studies are well recognized. Madigan et al. (69) showed that there were large differences in intake of some foods and in other lifestyle factors between those agreeing to take part and those refusing to take part in a study conducted in three regions in the United States that also reported on the association between folate intake and breast cancer risk (22). A Finnish case–control study of diet and breast cancer risk (70) that used two groups of control subjects (one population based, the second group consisting of women who were referred to the same examinations as the case subjects because of clinical suspicion of breast disease but who were later diagnosed as healthy) to estimate the impact of a breast cancer diagnosis on diet reporting found evidence for reporting bias that influenced some associations between diet and the risk of breast cancer, although folate intake was not specifically addressed.
Subgroup analyses increase the possibility of chance findings and are often uninformative. Several of the cohort studies included in our meta-analysis reported findings that suggested an interaction between alcohol and folate intake in breast cancer risk (33–35,39,40,44). A plausible hypothesis exists in which alcohol intake and inadequate dietary intake act synergistically to deplete serum folate levels and thus increase breast cancer risk (71). However, a randomized crossover trial in which women received three 8-week treatments of alcohol at 0, 15, and 30 g/d in random order found that moderate alcohol intake had no effect on serum folate concentrations (72). Results of subgroup analyses, such as those used to examine alcohol–folate interactions in breast cancer, have been shown to be unreliable: for continuous variables because the analyses will depend on arbitrary cutoff points and are thus liable to produce spurious results and because multiple testing increases the possibility of statistically significant findings (73).
One subgroup analysis that may be informative is the association between folate and breast cancer risk in pre- versus postmenopausal women. Cell proliferation in breast epithelial cells of premenopausal women is much higher than that in breast epithelial cells of postmenopausal women (74), and dividing and differentiating cells may be particularly susceptible to alterations in DNA synthesis, repair, and methylation. Because folate plays a role in these processes, if folate is also important in breast cancer risk, it is likely to be more strongly associated with premenopausal breast cancer than with postmenopausal breast cancer. However, we found no evidence from the cohort studies of a difference in the association between folate intake and breast cancer risk in pre- and postmenopausal women.
Dietary factors such as folate are strongly confounded by other dietary and lifestyle factors. In the Iowa Women's Health Study (35), higher folate intake was related to lower waist-to-hip ratio, higher alcohol intake, and greater use of hormone replacement therapy. There were also strong associations between the intakes of different B vitamins. Therefore, even when associations are observed between folate and cancer, such as in the case–control analysis in this study, it is difficult to determine whether the observed association is due to folate intake or to other confounding factors.
Associations between genetic variants and disease are not generally subject to the problem of confounding. In our meta-analysis, we found no association between the MTHFR C677T polymorphism and breast cancer risk. It has been hypothesized (27,30,38,45–58) that the thermolabile variant of MTHFR generated by the presence of the T allele at the C677T site may decrease the risk of developing cancer by providing more folate for DNA synthesis and repair or, conversely, may increase the risk of cancer by reducing the availability of methyl groups for DNA methylation. If both these mechanisms are in operation, then MTHFR C677T heterozygotes might be expected to have a lower risk of breast cancer than both TT and CC homozygotes. However, our meta-analysis found that the risk in heterozygotes was not different from that in TT and CC homozygotes. Similarly, there was no difference in breast cancer risk between CC versus TT homozygotes. In addition, we found that the studies that examined the interaction between MTHFR C677T genotype and folate intake obtained conflicting results. If folate intake is a risk factor for breast cancer, a functional polymorphism in a gene that influences a rate-limiting step in folate metabolism should be related to breast cancer risk. Thus, findings for the MTHFR C677T genotype and breast cancer do not support a role of folate in this disease. However, despite the large number of subjects included in the MTHFR C677T meta-analysis, the confidence intervals show that a small effect of the MTHFR C677T genotype on breast cancer risk cannot be ruled out. It is worth noting that Justenhoven et al. (57) found that functional polymorphisms in the methionine synthase and thymidylate synthase (TYMS) genes, which code for rate-limiting enzymes involved in methylation and DNA synthesis, respectively, were not associated with breast cancer risk in a relatively large case–control study that included 584 case subjects. Similarly, there was no association with a different polymorphism in the TYMS gene in the study by Grieu et al. (50).
Fortification of cereals and grain with folic acid began in 1996 in the United States and became mandatory in January 1998 in the United States and Canada (75,76). As a result of this policy, the average person residing in these countries consumed an additional 200 µg/d of dietary folate (77,78). From 1994 to 1998, the median serum folate level among US citizens increased from 12.6 to 18.7 µg (78). Folate supplementation at the time of conception has been shown to reduce the prevalence of neural tube defects in the offspring in randomized controlled trials (79), and the mandatory fortification with folate paralleled the decline observed in the incidence of neural tube defects of 19% and 48% in the United States and Canada during the 1990s (75,76). However, no decline in the incidence of breast cancer has been observed during the same time period; if anything, breast cancer incidence has increased (80). Although this increase could be attributed to greater detection rates, it could also be argued that the fortification occurred too recently to see a decrease in breast cancer risk, given the long latency period of breast cancer.
Evidence from animal studies shows that supplementation with folate may actually promote tumorigenesis in initiated cells. Two studies (81,82) carried out in Sprague–Dawley rats found that dietary folate supplementation at four times the basal requirement did not substantially modulate mammary tumorigenesis, whereas folate deficiency suppressed mammary tumorigenesis. These results are consistent with an earlier study (83) that examined the effect of dietary folic acid supplementation and deficiency in Fischer 344 rats. In that study, the incidence of mammary cancer was not associated with folate intake. However, rats that received no folic acid in their diets had lower tumor multiplicity and took 50% longer to develop palpable mammary tumors than those that received folate supplementation at either 20 or 40 mg.
In conclusion, we have reviewed the evidence from epidemiologic and genetic studies and found no consistent or reliable evidence to support a role of dietary folate in breast cancer prevention. The association between folate intake and breast cancer risk that has been observed in some case–control studies may be due to a combination of chance, bias, measurement error, and/or confounding. Thus, the results from these studies should not be overinterpreted, especially given the evidence that folate supplementation in rats with initiated breast cancer cells is harmful (81–83). Several randomized controlled trials are underway to determine whether taking folate supplements protects against coronary heart disease (84,85), and many of these trials will also be able to address the question of whether high folate intake protects against breast cancer. Additional follow-up studies of women who were randomly assigned to receive folic acid supplements during pregnancy, such as the study by Charles et al. (61), will highlight whether exposure to high levels of folate during this period is associated with breast cancer risk. Until such results are available, we conclude that there is no evidence that folate intake protects against breast cancer.
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NOTES |
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The authors had full responsibility for the study design, data collection and analyses, interpretation of the results, and the preparation of the manuscript
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Manuscript received March 6, 2006; revised August 24, 2006; accepted September 19, 2006.
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