Does a High Folate Intake Increase the Risk of Breast Cancer?

Although not uniformly consistent, epidemiologic studies generally suggest an inverse association between dietary intake and blood measurements of folate and breast cancer risk. However, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial has recently reported for the first time a potential harmful effect of high folate intake on breast cancer risk. In this study, the risk of developing breast cancer was significantly increased by 20% in women reporting supplemental folic acid intake ≥ 400 μg/d compared with those reporting no supplemental intake. Furthermore, although food folate intake was not significantly related to breast cancer risk, total folate intake, mainly from folic acid supplementation, significantly increased breast cancer risk by 32%. The data from the PLCO trial support prior observations made in epidemiologic, clinical, and animal studies suggesting that folate possesses dual modulatory effects on the development and progression of cancer depending on the timing and dose of folate intervention. Based on the lack of compelling supportive evidence, routine folic acid supplementation should not be recommended as a chemopreventive measure against breast cancer at present.     

The etiology of alcohol-induced breast cancer.

Breast cancer is the most common cancer in women in the United States, and it is second among cancer deaths in women. Results of most epidemiologic studies, as well as of most experimental studies in animals, have shown that alcohol intake is associated with increased breast cancer risk. Alcohol consumption may cause breast cancer through different mechanisms, including through mutagenesis by acetaldehyde, through perturbation of estrogen metabolism and response, and by inducing oxidative damage and/or by affecting folate and one-carbon metabolism pathways. Alcohol-metabolizing enzymes are present in human breast tissue. Acetaldehyde is a known, although weak, mutagen. However, results of some studies with human subjects implicate this agent in the context of genetic susceptibilities to increased ethanol metabolism. Reactive oxygen species, resulting from ethanol metabolism, may be involved in breast carcinogenesis by causing damage, as well as by generating DNA and protein adducts. Alcohol interferes with estrogen pathways in multiple ways, influencing hormone levels and effects on the estrogen receptors. With regard to one-carbon metabolism, alcohol can negatively affect folate levels, and the folate perturbation affects DNA methylation and DNA synthesis, which is important in carcinogenesis. Some study results indicate that genetic variants of one-carbon metabolism genes might increase alcohol-related breast cancer risk. For all these pathways, genetic polymorphisms might play a role in increasing further a woman's risk for breast cancer. Additional studies are needed to determine the relative importance of these pathways, as well as the modifying influence by genetic variation.     

Relationship of folate to colorectal and cervical cancer: review and recommendations for practitioners

Evidence suggests that folate may play a role in cancer prevention. A plausible mechanism for prevention lies in the integral role that folate plays in deoxyribonucleic acid (DNA) synthesis and methylation. DNA methylation most likely regulates gene expression. Abnormal methylation, specifically hypomethylation, has been associated with tumorigenesis. The availability of methyl groups needed for adequate DNA methylation may be negatively influenced by low folate status, alcohol intake, or genetic polymorphisms that affect folate metabolism. Observational studies evaluating the association between folate and risk for colorectal and cervical cancers or precancerous conditions have produced conflicting results, and clinical trial data are needed to confirm a cause-and-effect relationship. However, several studies show interesting associations between cancer risk and factors that influence methyl group availability. Although data relating folate to cancer risk remain equivocal, when coupled with the other potential health benefits associated with folate, evidence supports recommending that people consume folate-rich foods such as fruits and vegetables. People consuming alcohol on a daily basis may especially benefit from additional folate in their diets.     

Beneficial role for folate in the prevention of colorectal and breast cancer

Summary Folate is involved in the synthesis of nucleotides and amino acid metabolism such as methylation of homocysteine to methionine. Methionine is activated by adenosine triphosphate (ATP) to produce S-adenosylmethionine (SAM), the primary intracellular methyl donor. Thus, folate is essential for the synthesis, methylation, and repair of DNA. With regard to its biochemical function it has been hypothesized that a diminished folate status may contribute to carcinogenesis by alteration of gene expression and increased DNA damage. Animal and human studies support this hypothesis, particularly with respect to colorectal cancer. Epidemiological evidence for the association between folate status and cancer was first observed among ulcerative colitis patients. Several case-control studies demonstrated reduction in colorectal cancer risk with better folate status. Two large, prospective cohort studies support the concept that high folate intake is protective against colon cancer. In contrast to colorectal cancer, the potential association of folate status and risk has been less investigated in breast cancer. Recently, convincing epidemiological data establishing a positive effect of folate status on breast cancer risk were published. This review summarizes the epidemiological evidence for the association between folate status and colorectal and breast cancer risk. In addition, a short overview is given on the discussed mechanism(s) by which folate might be involved in carcinogenesis. Received: 6 October 2000, Accepted: 13 June 2001     

Environmental exposure to polychlorinated biphenyls and breast cancer risk

Breast cancer is a major public health problem in the United States and in most industrialized countries. Although epidemiologic studies have identified a number of established risk factors for this disease, these factors explain only a small proportion of breast cancer incidence. Environmental exposure has been implicated in breast cancer etiology because of the vast geographic variation in breast cancer incidence rates across countries and regions within countries. Further, the steady increase in breast cancer rates over the past decades points to a potential role of environmental exposure in its development. One suspected environmental factor is the polychlorinated biphenyls (PCBs), which were manufactured commercially for a variety of industrial applications from the 1930s until the 1970s. PCBs have been associated with estrogenic, tumor promoting, and immunosuppressive activities, all of which are relevant in the development of breast cancer. The purpose of this review is to summarize the growing body of epidemiological evidence on the association between environmental PCB exposure and breast cancer risk. Three major types of study design have been used to investigate such a relation: clinic-based case-control studies, retrospective case-control studies, and nested case-control studies. Although findings from clinic-based case-control studies tend to point to an adverse effect of high PCB body burden on risk, the results from the more methodologically sound retrospective and nested studies do not provide strong support for a role of PCBs in breast cancer development. The association between PCB exposure and risk among racially and genetically susceptible subgroups may warrant further investigation. Methodological challenges in the design and analysis of epidemiologic studies on PCBs and breast cancer risk are discussed.     

Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

BACKGROUND: Several epidemiologic studies suggest that higher folate intakes are associated with lower breast cancer risk, particularly in women with moderate alcohol consumption. OBJECTIVE: We investigated the association between dietary folate, alcohol consumption, and postmenopausal breast cancer in women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort. DESIGN: Dietary data were collected at study enrollment between 1993 and 2001. Folate content was assigned on the basis of prefortification (ie, pre-1998) databases. Of the 25 400 women participants with a baseline age of 55-74 y and with complete dietary and multivitamin information, 691 developed breast cancer between September 1993 and May 2003. We used Cox proportional hazard models with age as the underlying time metric to generate hazard ratios (HRs) and 95% CIs. RESULTS: The adjusted HRs were 1.19 (95% CI: 1.01, 1.41; P for trend = 0.04) for women reporting supplemental folic acid intake >/=400 mug/d compared with subjects reporting no supplemental intake. Comparison of the highest with the lowest quintile gave adjusted HRs of 1.04 (95% CI: 0.83, 1.31; P for trend = 0.56) and 1.32 (95% CI: 1.04, 1.68; P for trend = 0.03) for food and total folate intake, respectively. Alcohol consumption was positively associated with breast cancer risk (highest compared with lowest quintile: HR = 1.37; 95% CI: 1.08, 1.76; P for trend = 0.02); the risk was greatest in women with lower total folate intake. CONCLUSIONS: Our results do not support the hypothesis that high folate intake reduces breast cancer risk; instead, they suggest that a high intake, generally attributable to supplemental folic acid, may increase the risk in postmenopausal women. However, our results confirm previous studies showing positive associations between moderate alcohol consumption and breast cancer.     

Interaction of nitrate and folate on the risk of breast cancer among postmenopausal women

Ingested nitrate can be endogenously reduced to nitrite, which may form N-nitroso compounds, known potent carcinogens. However, some studies have reported no or inverse associations between dietary nitrate intake and cancer risk. These associations may be confounded by a protective effect of folate, which plays a vital role in DNA repair. We evaluated the interaction of dietary and water nitrate intake with total folate intake on breast cancer risk in the Iowa Women's Health Study. Dietary intake was assessed at study baseline. Nitrate intake from public water was assessed using a historical database on Iowa municipal water supplies. After baseline exclusions, 34,388 postmenopausal women and 2,875 incident breast cancers were included. Overall, neither dietary nor water nitrate was associated with breast cancer risk. Among those with folate intake ≥400 μg/day, breast cancer risk was significantly increased in public water users with the highest nitrate quintile (HR = 1.40, 95% CI = 1.05-1.87) and private well users (HR = 1.38, 95% CI = 1.05-1.82) compared to public water users with the lowest nitrate quintile; in contrast, there was no association among those with lower folate intake. Our findings do not support a previous report of increased risk of breast cancer among individuals with high dietary nitrate but low folate intake.     

Medical hypothesis: xenoestrogens as preventable causes of breast cancer.

Changes in documented risk factors for breast cancer and rates of screening cannot completely explain recent increases in incidence or mortality. Established risk factors for breast cancer, including genetics, account for at best 30% of cases. Most of these risk factors can be linked to total lifetime exposure to bioavailable estrogens. Experimental evidence reveals that compounds such as some chlorinated organics, polycyclic aromatic hydrocarbons (PAHs), triazine herbicides, and pharmaceuticals affect estrogen production and metabolism and thus function as xenoestrogens. Many of these xenoestrogenic compounds also experimentally induce mammary carcinogenesis. Recent epidemiologic studies have found that breast fat and serum lipids of women with breast cancer contain significantly elevated levels of some chlorinated organics compared with noncancer controls. As the proportion of inherited breast cancer in the population is small, most breast cancers are due to acquired mutations. Thus, the induction of breast cancer in the majority of cases stems from interactions between host factors, including genetics and environmental carcinogens. We hypothesize that substances such as xenoestrogens increase the risk of breast cancer by mechanisms which include interaction with breast-cancer susceptibility genes. A series of major epidemiologic studies need to be developed to evaluate this hypothesis, including studies of estrogen metabolism, the role of specific xenoestrogenic substances in breast cancer, and relevant genetic-environmental interactions. In addition, experimental studies are needed to evaluate biologic markers of suspect xenoestrogens and biologic markers of host susceptibility and identify pathways of estrogenicity that affect the development of breast cancer. If xenoestrogens do play a role in breast cancer, reductions in exposure will provide an opportunity for primary prevention of this growing disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidemiologic evidence suggests that dietary phytoestrogen intake is associated with reduced risk of breast, endometrial, and prostate cancers

Phytoestrogens are natural estrogen-like plant substances. The possible protective effect of phytoestrogens on cancer risk, particularly on hormone-related cancers, has been the focus of many epidemiologic studies during the last 2 decades. We performed a qualitative review of the epidemiologic literature published in the English language and identified on MEDLINE from 1966 until 24 September 2006 on (1) dietary intake of soy, isoflavones, or lignans; (2) urinary excretion of isoflavones or lignans; (3) blood measurements of isoflavones or lignans in relation to breast, prostate, and endometrial cancer risk. Epidemiologic data do seem to support a small protective effect of isoflavones on breast cancer risk, although timing of exposure and the mechanisms of isoflavones at physiologic levels need to be further explored. The epidemiologic evidence to date is conflicting regarding lignans and breast cancer, but recent studies suggest that the effect may be restricted to premenopausal women, differ by estrogen receptor status, and be modified by diet-gene interactions. The 3 case-control studies on dietary intake of phytoestrogens and endometrial cancer risk have provided some evidence for a protective effect, but more prospective data are needed. There is some epidemiologic evidence for a protective effect of soy or isoflavones on prostate cancer, but corresponding data for lignans are inconclusive. Recent data indicate that diet-gene interactions may modify the effect of phytoestrogens on prostate cancer risk. Prospective studies on dietary lignans in relation to prostate cancer risk are lacking.     

Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies

A growing body of evidence implicates alcohol intake as a risk factor for colorectal cancer. Until recently, most of the data were based on epidemiologic data that examined alcohol intake in relation to risk of colorectal neoplasia, but the evidence has now been broadened by recent molecular studies on mechanisms. In particular, a number of observations strongly support a role for alcohol acting through disruptions in one-carbon metabolism. Excessive alcohol intake is a fairly consistent risk factor for colorectal neoplasia in most studies, and studies show much higher risks of colorectal neoplasia in those with high alcohol and low folate than with high alcohol or low folate individually. Interactions between high alcohol-low folate and the MTHFR677TT genotype with risk of colorectal neoplasia suggest that alcohol is acting through its effects on one-carbon metabolism because the combination of high alcohol-low folate and the MTHFR677TT genotype are related to markedly elevated serum levels of homocysteine and to DNA hypomethylation. In addition, in Japanese studies, consumers of alcohol possessing the ALDH2*2 allele, who have very elevated levels of acetaldehyde, are at high risk for colorectal cancer. The relatively high prevalence of the ALDH2*2 allele may thus account for the stronger association between alcohol and colorectal neoplasia that is frequently observed in studies in Japanese populations. Further research integrating studies with more detailed data on alcohol intake levels and patterns, folate and other related nutrient status, and relevant genotypes may help clarify unresolved questions regarding the health consequences of moderate to high alcohol drinking.     

A prospective study of folate intake and the risk of pancreatic cancer in men and women

Laboratory and human studies suggest that folate intake may influence the risk of some cancers. However, prospective information about the relation between folate intake and the risk of exocrine pancreatic cancer is limited. The authors examined the relation of dietary folate intake to the risk of pancreatic cancer in two large prospective US cohorts. Folate intake was assessed by food frequency questionnaire in 1984 in women and in 1986 in men. Multivariate relative risks were adjusted for age, energy intake, cigarette smoking, body mass index, diabetes, and height. During 14 years' follow-up in each cohort, 326 incident cases of pancreatic cancer were identified. Compared with participants in the lowest category of folate intake, participants in increasing 100- micro g categories of total energy-adjusted folate intake had pooled multivariate relative risks for pancreatic cancer of 1.08, 1.10, and 1.03 (95% confidence interval: 0.74, 1.43; p(trend) = 0.99). For energy-adjusted folate from food, the pooled relative risks for increasing 100- micro g categories of intake were 0.81, 0.89, and 0.66 (95% confidence interval: 0.42, 1.03; p(trend) = 0.12). There was no statistical interaction between folate intake and methionine, alcohol, fat, or caffeine. The results from these two large prospective cohorts do not support a strong association between energy-adjusted folate intake and the risk of pancreatic cancer.     

Vitamin B12 Deficiency: A New Risk Factor for Breast Cancer?

A prospective epidemiologic study found a threshold level for serum vitamin B12, below which an increased risk of breast cancer among postmeno-pausal women was observed. This is the first observation to suggest that B12 status may influence breast carcinogenesis and therefore may be a modifiable risk factor for breast cancer prevention.     

High-folate diets and breast cancer survival in a prospective cohort study

Recent evidence suggests that adequate dietary folate may attenuate the risk of breast cancer associated with intake of alcohol. However, patients with breast cancer have been commonly treated with antifolate chemotherapies. The present analysis was performed to test the hypothesis that high folate intake may diminish the effectiveness of chemotherapy and, therefore, adversely influence survival. Women at risk of postmenopausal breast cancer (n = 37,105) participated in the Iowa Women's Health Study. Total folate intake (diet + supplements) was estimated from a food frequency questionnaire administered at baseline in 1986 and categorized into tertiles. From all incident breast cancer cases ascertained in the cohort, we selected those with a diagnosis between 1986 and 1994, chemotherapy as first course of treatment, and adequate diet assessment. Mortality was determined through the State Health Registry of Iowa and the National Death Index. Cox regression was used to estimate survival while adjusting for important covariates. Through 14 yr of follow-up, 80 deaths occurred among the 177 breast cancer cases treated with chemotherapy. Among these patients, high folate intake was not associated with worse survival. After adjustment for age, extent of disease, total calories, alcohol, and estrogen receptor status, women with total folate intake in the highest tertile had a mortality risk ratio of 0.88 (95% confidence interval = 0.44-1.76) compared with cases in the lowest tertile of folate. These findings, although preliminary, afford some reassurance that folate supplementation is unlikely to have a significant adverse effect on survival after chemotherapy for breast cancer.     

Folate intake and pancreatic cancer risk: an overall and dose–response meta-analysis

Objective

Inconsistent findings of association between supplemental folate consumption and pancreatic cancer risk have been observed in the literature. This study aims to summarize the relationship between folate intake and risk of pancreatic cancer.

Study design

Pertinent studies published before November 2011 were identified by searching PubMed and Embase and by reviewing the reference lists of retrieved articles. The summary relative risks were estimated by the random effects model. A linear regression analysis of the natural logarithm of the relative risk (RR) was carried out to assess a possible dose–response relationship between folate intake and pancreatic cancer risk.

Results

Ten studies on dietary and supplemental folate intake and pancreatic cancer (4 case–control and 6 cohort studies) were included in the meta-analysis. The pooled RRs of pancreatic cancer for the highest vs lowest categories of dietary folate intake and supplemental folate intake were 0.66 (95% CI: 0.49–0.88) and 1.08 (95% CI, 0.82–1.41), respectively. The dose–response meta-analysis indicated that a 100 μg/day increment in dietary folate intake conferred a RR of 0.93 (95% CI: 0.90–0.97). These findings support the hypothesis that dietary folate may play a protective role in carcinogenesis of pancreatic cancer.     

Weight reduction for breast cancer prevention by restriction of dietary fat and calories: rationale, mechanisms and interventions

A large body of epidemiologic evidence and data drawn from animal feeding studies have led to the feasibility testing of clinical breast cancer prevention trials based on the restriction of dietary fat intake. The animal data strongly suggest that restricting calories as well as fat inhibits breast cancer promotion. Body fat correlates with dietary fat intake in human populations. Obese postmenopausal women have increased levels of circulating bioavailable estrogen capable of promoting breast cancer growth. We propose that restriction of dietary fat intake will decrease total calorie intake and result in a loss of body fat in postmenopausal women. This loss of fat will decrease estrogen production from adrenal androgens and increase bioavailable estrogen, leading to decreased promotion of estrogen-dependent breast tumors. Intervention programs targeted at weight reduction via restriction of calories, reduction of dietary fat and increased physical activity are logical, practical and measurable strategies for reducing the risk of breast cancer in women at moderate to increased risk. Failure to account for variations in adherence to a restricted-fat diet in past feasibility studies has cast doubt on the hypothesis that restricting dietary fat intake can be utilized to reduce the risk of breast cancer. Current studies examining nutritional, hormonal and physiologic data in conjunction with evidence of adherence to dietary and lifestyle change will likely clarify the hormonal and physiologic effects of this potential nutritional strategy for breast cancer prevention.     

Folate and carcinogenesis: an integrated scheme

Collectively, the evidence from epidemiologic, animal and human studies strongly suggests that folate status modulates the risk of developing cancers in selected tissues, the most notable of which is the colorectum. Folate depletion appears to enhance carcinogenesis whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. The means by which this modulation of cancer risk is mediated is not known with certainty, but there are several plausible mechanisms which have been described. Folate plays a major role in the formation of S-adenosylmethionine, the universal methyl donor, as well as in the formation of purine and thymidine synthesis for DNA and RNA. Therefore, most mechanistic studies performed to date have focused on alterations in DNA methylation, disruption of DNA integrity and disruption of DNA repair, all of which have been observed with folate depletion. These aberrations in DNA are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes. Recently, the role of a common polymorphism of the methylenetetrahydrofolate reductase gene has been highlighted as well. This review presents those mechanisms which are the most likely candidates to explain folate's effects and it proposes an integrated scheme to explain how these mechanisms might interact.     

Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women.

Low B-vitamin intake may increase risk of breast cancer through decreased DNA repair capacity. Alcohol intake increases risk for breast cancer, with evidence from prospective studies of an interaction between alcohol and folate. We explored dietary intake of folate and other B vitamins with risk of breast cancer in a cohort study of 34,387 postmenopausal women. To measure diet, we mailed a food frequency questionnaire; we estimated nutrient intakes and categorized them into four levels: <10th, 11th-30th, 31st-50th, and >50th percentiles. Through 12 years of follow-up, we identified 1,586 cases of breast cancer in the cohort at risk. We estimated relative risks (RRs) and 95% confidence intervals (CIs) through Cox regression models adjusted for age, energy, and other risk factors. Women in the lowest 10th percentile of folate intake from diet alone were at modestly increased risk of breast cancer relative to those above the 50th percentile: RR = 1.21 (95% CI = 0.91--1.61). We examined the joint association of folate intake and alcohol use on risk of breast cancer, with the reference group defined as women with high folate (>50th percentile) and no alcohol use. The RRs of breast cancer associated with low dietary folate intake were 1.08 (95% CI = 0.78--1.49) among nondrinkers, 1.33 (95% CI = 0.86--2.05) among drinkers of < or = 4 gm per day, and 1.59 (95% CI = 1.05--2.41) among drinkers of > 4 gm per day. These results suggest that the risks of postmenopausal breast cancer may be increased among women with low intakes of folate if they consume alcohol-containing beverages.     

High-Density Lipoprotein and Prostate Cancer: An Overview

Prostate cancer is a common disease in modern, developed societies and has a high incidence and mortality. High-density lipoprotein cholesterol (HDL-C) has recently received much attention as a possible risk marker of prostate cancer development and prognosis. In the present article, we summarized findings from epidemiologic studies of the association between HDL-C and prostate cancer. Low HDL-C level was found to be a risk and prognostic factor of prostate cancer in several epidemiologic studies, although the overall linkage between HDL and prostate cancer has not been definitively established. The mechanisms for this association remain uncertain; however, limited data from experimental studies imply a possible role of HDL in the pathophysiology of prostate cancer. More epidemiologic research, in combination with experimental studies, is needed in this field.Key words: epidemiology, HDL-cholesterol, apoA-I, prostate tumor     

Mammary gland mass and breast cancer risk.

Evidence indicates that early life events and conditions, possibly extending to the intrauterine stages of life, and including energy restriction in early life, affect the risk of breast cancer. The mechanism of this effect is likely to be through a reduction in mammary gland mass and, inferentially, the total number of ductal stem cells. The evidence derives from epidemiologic and animal studies. It can explain certain epidemiologic findings that cannot be accounted for by more established breast cancer risk factors, including the more frequent occurrence of breast cancer in the left breast and the higher incidence of this disease among caucasian women than among Asian women in Asia.     

Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark

OBJECTIVE: There is consistent evidence that alcohol increases the risk of breast cancer. It has been suggested that the increased risk associated with alcohol intake may be reduced by adequate intake of folate. Since many women consume alcohol, detection of a risk-reducing mechanism would have major public health implications. DESIGN: We therefore evaluated the possible interaction between alcohol and folate in a paired nested case-control study among postmenopausal women. SETTING: A total of 24 697 postmenopausal women were included in the 'Diet, Cancer and Health' follow-up study between December 1993 and May 1997. The cohort was followed until December 2000. The study included 388 cases of breast cancer and 388 randomly selected controls were used to estimate the breast cancer incidence rate ratio (IRR) in conditional logistic regression analysis. RESULTS: A previously established association between alcohol intake and risk of breast cancer was present mainly among women with low folate intake. An IRR of 1.19 (95% CI: 0.99-1.42) per 10 g average daily alcohol intake was found for women with a daily folate intake below 300 mug, while among women with a folate intake higher than 350 mug, we could not show an association between the alcohol intake and the breast cancer incidence rate (e.g. folate intake >400 mug; IRR of 1.01 (95% CI: 0.85-1.20)). CONCLUSION: The findings support the evidence that adequate folate intake may attenuate the risk of breast cancer associated with high alcohol intake. SPONSORSHIP: The Danish Cancer Society.