CEBP CTRC-AACR San Antonio Breast Cancer Symposium Cancer Health Disparities Conference 2009
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, S. M.
Right arrow Articles by Willett, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, S. M.
Right arrow Articles by Willett, W. C.
Cancer Epidemiology Biomarkers & Prevention Vol. 14, 2004-2008, August 2005
© 2005 American Association for Cancer Research

Folate Intake and Risk of Breast Cancer Characterized by Hormone Receptor Status

Shumin M. Zhang1,3, Susan E. Hankinson2,3, David J. Hunter2,3,4, Edward L. Giovannucci2,3,4, Graham A. Colditz2,3 and Walter C. Willett2,3,4

1 Division of Preventive Medicine, 2 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; Departments of 3 Epidemiology and 4 Nutrition, Harvard School of Public Health, Boston, Massachusetts

Requests for reprints: Shumin M. Zhang, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215. Phone: 617-278-0856; Fax: 617-731-3843. E-mail: Shumin.Zhang{at}channing.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Folate plays an important role in DNA methylation, and aberrant methylation of the estrogen receptor (ER) gene may be related to the loss of ER gene expression in breast tumors. Thus, deficient folate status has been hypothesized to be associated primarily with ER gene–negative breast tumors, but data relating folate intake to breast cancer risk according to ER status are sparse. We conducted a prospective cohort analysis of folate intake among 88,744 women in the Nurses' Health Study who completed a food frequency questionnaire in 1980 and every 2 to 4 years thereafter. During 20 years of follow-up, 2,812 ER+ and 985 ER– invasive breast cancer cases were documented. Higher total folate intake was significantly associated with lower risk of developing ER– but not ER+ breast cancer; the multivariable relative risks (RR) and 95% confidence intervals (95% CI) comparing the highest to the lowest quintile were 0.81 (0.66-0.99) for ER– tumors and 1.00 (0.89-1.14) for ER+ tumors. The inverse association between total folate intake and ER– breast cancer was mainly present among women consuming at least 15 g/d of alcohol (multivariable RR, 0.46; 95% CI, = 0.25-0.86; top versus bottom quintile). These findings support the hypothesis that higher folate intake reduces the risk of developing ER– breast cancer. Ensuring adequate folate intake seems particularly important for women at higher risk of breast cancer because of alcohol consumption.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A majority of breast tumors express the estrogen receptor (ER) gene and synthesize ER protein, but about one third of breast tumors lack ER protein, rarely respond to hormone therapy, and are associated with a poorer prognosis (1). Gene expression can be modulated by epigenetic mechanisms; alterations in DNA methylation patterns are frequently seen in tumor cells, with wide areas of hypomethylation along the genome accompanied by localized areas of hypermethylation at specific sites, such as cytosine-guanine-rich areas, termed CpG islands (2-5). Lack of ER gene transcription, as seen in ER– breast tumors, may be due to extensive methylation of the ER gene CpG island in the 5' regulatory region and first exon (6-11). Although hypermethylation of the CpG island was found to be involved in silencing progesterone receptor (PR) gene expression (9), reactivation of PR gene expression was independent of demethylation (12), suggesting that methylation may play a smaller role in regulating PR gene expression.

Folate in the form of methyltetrahydrofolate participates in regeneration of methionine by providing a methyl group to homocysteine to form methionine and eventually S-adenosylmethionine (13). S-adenosylmethionine can serve as a methyl donor for DNA methylation (14). Low folate status may thus alter DNA methylation and thereby influence gene stability and expression (14). Thus, as hypothesized by Zhu and Williams (15), low folate status may be associated primarily with ER gene–negative breast tumors. Folate also functions as a coenzyme in the synthesis of purines and thymidylate for DNA. Diminished folate status may result in misincorporation of uracil into DNA, leading to chromosome breaks and disruption of DNA repair (14, 16, 17).

Several epidemiologic investigations (18-27) including three large prospective cohorts, the Nurses' Health Study (18, 19), the Canadian National Breast Screening Study (20), the Iowa Women's Health Study (21), suggest that adequate folate intake or blood levels may be important in the prevention of breast cancer, particularly among women who regularly consume alcohol (18-22, 26). Alcohol is a known folate antagonist (28, 29) and thus could plausibly increase the requirement for folate intake. Because of limited progress in the identification of risk factors for ER– breast cancer, we conducted a prospective analysis to evaluate folate intake in relation to breast cancer risk according to ER status in the Nurses' Health Study.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
The Nurses' Health Study was established in 1976 when 121,700 female registered nurses ages 30 to 55 years living in 11 states completed a mailed questionnaire about their medical history and lifestyle. Follow-up questionnaires have been sent to cohort members biennially to update health-related information and to ascertain newly diagnosed diseases including breast cancer. Dietary information was collected using the food frequency questionnaires in 1980, 1984, 1986, 1990, 1994, and 1998. The study was approved by the Use of Human Subjects in Research Committee at the Brigham and Women's Hospital.

Semiquantitative Food Frequency Questionnaires
The questionnaires assessed the average consumption over the past year of a specific amount of each food and allowed nine responses, ranging from "never" to "six or more times per day." Nutrient intake was calculated by multiplying the frequency response by the nutrient content of the specified portion sizes. Total alcohol intake was the sum of the alcohol content contributed from beer, wine, and liquor, assuming 12.8 g of ethanol for 360 mL (12 oz) of beer, 11.0 g for 120 mL (4 oz) of wine, and 14.0 g for 45 mL (1.5 oz) of liquor. Duration, brand, and type of multivitamin supplement use were updated biennially. A comprehensive database on the content of vitamins of the multivitamin preparations was developed.

The validity and reliability of the food frequency questionnaires used in the Nurses' Health Study have been described in detail elsewhere (30-33). In a sample of 188 participants, the correlation coefficients between folate intake calculated from the 1980 dietary questionnaire and erythrocyte folate concentrations in 1987 were 0.55 for total folate and 0.38 for dietary folate (34). In a sample of 712 participants who provided blood specimens during 1989 to 1990 and served as control subjects in a nested case-control study of breast cancer, the correlation coefficients between folate intakes calculated from the 1990 food frequency questionnaire and plasma levels were 0.55 for total folate and 0.35 for dietary folate (19). In addition, in a sample of 173 participants, alcohol intake calculated from the 1984 dietary questionnaire was highly correlated with the 1980 four 1-week diet records (r = 0.84) and plasma high-density lipoprotein cholesterol levels, which are known to be influenced by alcohol (r = 0.40; ref. 35).

Ascertainment of Breast Cancer Cases
Incident cases of breast cancer were first identified by self-report on each biennial questionnaire. Deaths in the cohort were identified by reports from family members, the postal service, and a search of the National Death Index, and we estimate that 98% of all deaths were identified (36). Women (or their next of kin if they had died) who reported breast cancer were asked for permission to obtain hospital records and pathology reports relevant to diagnosis. Self-reported breast cancer cases were confirmed by medical personnel who reviewed the records. Information on ER and PR status was extracted from the records. A total of 4,422 invasive cases of breast cancer were identified from 1980 to 2000 among 88,744 women who completed the baseline food frequency questionnaire, had total energy intake within the range of 500 to 3,500 kcal/d, and were free of cancer in 1980. Of these cases, 2,812 (63.6%) were ER+, 985 (22.3%) were ER–, 2,256 (51.0%) were PR+, and 1,361 (30.8%) were PR–; ER status was not available for 625 cases (14.1%) and PR status was not available for 805 cases (18.2%).

Statistical Analysis
Person-years for each participant were calculated from the date of returning the 1980 questionnaire to the date of diagnosis of breast cancer, death, or May 31, 2000, whichever came first. Folate intake was adjusted for total energy using the residual method (33) and categorized into quintiles. The cumulative average intakes of folate and alcohol from all available questionnaires were used to best represent long-term intakes (37). In this analysis, we modeled the incidence of breast cancer in relation to the cumulative average of dietary intake from all available dietary questionnaires up to the start of each 2-year follow-up interval (37). For example, the incidence of breast cancer during the 1980 through 1984 time period was related to the dietary information from the 1980 questionnaire, and the incidence of breast cancer during the 1984 through 1986 time period was related to the average intake from the 1980 and 1984 questionnaires. The incidence rate was calculated by dividing the number of cases by person-years of follow-up in each category. The relative risk (RR) was calculated as the rate in a specific category divided by that in the reference category, with adjustment for 5-year age categories by the Mantel-Haenszel method (38). In multivariable analysis using pooled logistic regression with 2-year time increments (39, 40), we simultaneously adjusted for age (5-year age categories), period of follow-up (ten 2-year periods), age at menarche (≤12, 13, or ≥14 years), age at first birth (≤24, 25-29, or ≥30 years), parity (0, 1 or 2, 3, or 4, or ≥5 births), history of breast cancer in mother or a sister (yes or no), history of benign breast disease (yes or no), alcohol intake (0, 0.1-4.9, 5.0-14.9, 15.0-29.9, or ≥30 g/d), body mass index at age 18 years (<20, ≥20 to <22, ≥22 to <24, ≥24 to <27, or ≥27 kg/m2), weight change from age 18 years to present (loss >2.0, loss or gain of 2.0, gain 2.1-5.0, gain 5.1-10.0, gain 10.1-20.0, gain 20.1-25.0, or gain >25.0 kg), height in inches (continuous), age at menopause (<45, 45-49, 50-54, or ≥55 years), menopausal status (premenopausal, postmenopausal, or uncertain), and postmenopausal hormone use (premenopausal, uncertain, never, past <5 years, past ≥5 years, current <5 years, current ≥5 years). Information on age, weight change from age 18 years to present, age at menopause, menopausal status, postmenopausal hormone use, alcohol intake, family history of breast cancer, and history of benign breast disease was updated every 2 to 4 years. For all RRs, we calculated 95% confidence intervals (95% CI).

In additional analyses, we stratified by alcohol intake (<15 and ≥15 g/d, approximately one drink) because alcohol intake has been shown to modify the association between folate and breast cancer risk in our earlier studies (18, 19). All analyses were conducted according to ER or PR status of breast tumors. Tests for trend were done by using the median value of each category of the cumulative average nutrient intake as a continuous variable. A test for the difference in the estimates of folate intake (median values for each quintile as a continuous variable) for ER– versus ER+ breast tumors was conducted by using the squared T statistic, which has a {chi}2 distribution with one degree of freedom. All P values were two tailed.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Tables 1 and 2 present RRs and 95% CIs for intakes of total folate (from foods and supplements) and dietary folate (from foods only) by ER or PR status of breast tumors. The RRs from age-adjusted analyses were similar to those from multivariable analyses with additional adjustments for other risk factors for breast cancer. Higher intake of total folate was associated with significantly lower risk of developing ER– but not ER+ breast cancer (Table 1). The multivariable RRs and 95% CIs comparing the highest with the lowest quintile of total folate intake were 0.81 (0.66-0.99; Ptrend = 0.03) for ER– tumors and 1.00 (0.89-1.14; Ptrend = 0.83) for ER+ tumors. The difference in results for ER– versus ER+ breast tumors was marginally significant for total folate intake (P = 0.07). However, dietary folate intake was not associated with risk of developing ER– breast tumors but was associated with significant but small increased risk of developing ER+ breast tumors. The multivariable RRs and 95% CIs comparing the highest to the lowest quintile of dietary folate intake were 0.97 (0.79-1.18; Ptrend = 0.34) for ER– tumors and 1.15 (1.01-1.30; Ptrend = 0.05) for ER+ tumors. Excluding folate supplement users in the analysis for dietary folate intake did not appreciably change the results (data not shown). Neither total nor dietary intakes of folate were associated with risk of developing either PR– or PR+ breast tumors (Table 2).


View this table:
[in this window]
[in a new window]
  		Table 1. RR and 95% CI of breast cancer according to quintiles of cumulative updated intake of folate, by tumor ER status in the Nurses' Health Study, 1980-2000

 

View this table:
[in this window]
[in a new window]
  		Table 2. RR and 95% CI of breast cancer according to quintiles of cumulative updated intake of folate, by tumor PR status in the Nurses' Health Study, 1980-2000

 
When we further examined the associations between folate intake and breast cancer risk stratified by alcohol intake, we found that the inverse association between total folate intake and ER– breast cancer was mainly present among women consuming at least 15 g/d of alcohol (Table 3). The multivariable RRs and 95% CIs of ER– tumors comparing the highest to the lowest quintile of total folate intake were 0.46 (0.25-0.86) among women consuming at least 15 g/d of alcohol and 0.88 (0.71-1.10) among women consuming less than 15 g/d of alcohol. The difference in estimates for ER– versus ER+ breast tumors among women consuming at least 15 g/d of alcohol was marginally significant for total folate (P = 0.07). Dietary folate intake was also associated with marginally significant lower risk of developing ER– breast cancer among women consuming at least 15 g/d of alcohol (multivariable RR, 0.66; 95% CI, 0.36-1.21; Ptrend = 0.06; top versus bottom quintile). However, dietary folate intake was associated with marginally significant higher risk of developing ER+ breast cancer among women consuming <15 g/d of alcohol (multivariable RR, 1.16; 95% CI, 1.02-1.33; Ptrend = 0.04; top versus bottom quintile). Neither total nor dietary intakes of folate were associated with risk of developing either PR– or PR+ breast tumors even according to alcohol consumption (Table 4).


View this table:
[in this window]
[in a new window]
  		Table 3. Multivariable adjusted RR and 95% CI of breast cancer according to quintiles of cumulative updated intake of folate, by alcohol intake and tumor ER status in the Nurses' Health Study, 1980-2000

 

View this table:
[in this window]
[in a new window]
  		Table 4. Multivariable adjusted RR and 95% CI of breast cancer according to quintiles of cumulative updated intake of folate, by alcohol intake and tumor PR status in the Nurses' Health Study, 1980-2000

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this large prospective study, higher total folate intake was associated with significantly lower risk of developing ER– breast cancer among women. The inverse association between total folate intake and risk of ER– breast cancer was particularly strong among women who regularly consumed alcohol. The prospective design in this study minimizes the possibility that our findings are due to methodologic biases. Because comprehensive risk factors for breast cancer are available in this study and controlling for them had minimal effect on the RRs, our results are also unlikely to be explained by residual confounding by these factors.

Folate plays an important role in DNA methylation (14). ER CpG island methylation has been associated with lack of ER gene expression in breast cancer cell lines and primary breast tumors (6-11). In addition, absence of ER gene expression in ER– breast cancer cells has been associated with increased mRNA level and activity of DNA methyltransferase, an enzyme that methylates cytosine to 5-methylcytosine (7). Upon treatment with demethylating agents, the ER CpG island in ER– breast cancer cell lines is partially demethylated; such changes are correlated with reexpression of the ER gene and production of ER protein (8). In animal studies, folate/methyl-deficient diets increase the activity of DNA methyltransferase (41, 42). Furthermore, in a case-control study among African American women, lower folate intake was associated with 2-fold higher risk of breast tumors with a methylated ER{alpha} gene but not those with an unmethylated ER{alpha} gene (43). Our finding that total folate intake was primarily associated with lower risk of developing ER– breast tumors is consistent with these experimental and epidemiologic data and supports the hypothesis that low folate status promotes breast carcinogenesis at least in part through its influence on DNA methylation. Thus, adequate folate intake may be primarily important for preventing ER– breast tumors.

In contrast to total folate, data suggest a small positive association between dietary folate intake and risk of developing ER+ breast cancer, which was largely limited to women who consumed <15 g/d of alcohol. The difference in findings between total folate and dietary folate according to ER status is intriguing and merits further investigations. This small positive association associated with intake of dietary folate is unlikely to be explained by folate because this was not observed for intake of total folate, which contains folic acid supplements with much higher bioavailability (44). Alternative explanations are that dietary folate may merely serve as a marker for other factors that are correlated with dietary folate intake or it was a result of chance.

Several previous investigations including the Nurses' Health Study cohort (18, 19), the Canadian National Breast Screening Study cohort (20), the Iowa Women's Health Study cohort (21), and two case-control studies in Italy and Switzerland (22, 26) have found that the inverse association between folate intake or plasma levels and breast cancer risk was strong among women consuming alcohol intake. However, the American Cancer Society Cancer Prevention Study II Nutrition Cohort has reported no association between folate intake and risk of breast cancer even among women who consumed alcohol (45). Alcohol may perturb folate metabolism through reducing intestinal absorption, increasing renal excretion (29), inhibiting methionine synthase in the liver (46, 47), directly destroying folate (48), or interacting with tetrahydrofolate (46, 49). In the Iowa Women's Health Study, the only published cohort study that has examined the interaction of folate intake, alcohol, and risk of breast cancer by hormone receptor status, there was no appreciable association with risk of ER+ tumors at all levels of folate and alcohol, but there was an elevated risk of ER– tumors among women who had low intake of total folate and high intake of alcohol (50). We also observed a similar pattern for the effects of total folate intake stratified by alcohol according to ER status. Both studies found that the association between folate intake and breast cancer risk did not seem to differ according to PR status, suggesting the effects of folate may be more specific for ER. The consistence in findings from two large cohorts suggests such findings are unlikely to be explained by chance.

A potential limitation of this study is that data on the presence or absence of hormone receptors were determined from laboratories affiliated with hospitals where breast cancer cases were diagnosed and not from a single reference laboratory. However, the measurement of hormone receptors has been standardized clinically. Due to the use of a prospective design, the measurement error associated with the use of hormone receptor data from various hospitals is likely to be nondifferential and would tend to weaken the associations. Another potential limitation of this study is that ER status was not available for 14.1% of cases and PR status was not available for 18.2% of cases. However, folate intake before diagnosis is unlikely to be the indication for the availability of hormone receptor status. This small proportion of cases without hormone receptor data is thus unlikely to affect the associations appreciably.

In summary, our findings support the hypothesis that higher folate intake reduces the risk of developing ER– breast cancer. Ensuring adequate folate intake seems particularly important for women at higher risk of breast cancer due to alcohol consumption.


   Footnotes
 
Grant support: NIH grant CA87969, U.S. Army Medical Research and Materiel Command grant DAMD-17-02-1-0692, National Cancer Institute Career Development Award CA096619 (S.M. Zhang), and American Cancer Society Clinical Research Professorship (G.A. Colditz).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/31/05; revised 5/ 4/05; accepted 5/12/05.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Thorpe SM. Estrogen and progesterone receptor determinations in breast cancer. Technology, biology and clinical significance. Acta Oncol 1988;27:1–19.[Medline]
  2. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999;21:163–7.[CrossRef][Medline]
  3. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000;16:168–74.[CrossRef][Medline]
  4. Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 2001;20:3139–55.[CrossRef][Medline]
  5. Wajed SA, Laird PW, DeMeester TR. DNA methylation: an alternative pathway to cancer. Ann Surg 2001;234:10–20.[CrossRef][Medline]
  6. Piva R, Rimondi AP, Hanau S, et al. Different methylation of oestrogen receptor DNA in human breast carcinomas with and without oestrogen receptor. Br J Cancer 1990;61:270–5.[Medline]
  7. Ottaviano YL, Issa JP, Parl FF, Smith HS, Baylin SB, Davidson NE. Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor in human breast cancer cells. Cancer Res 1994;54:2552–5.[Abstract/Free Full Text]
  8. Ferguson AT, Lapidus RG, Baylin SB, Davidson NE. Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res 1995;55:2279–83.[Abstract/Free Full Text]
  9. Lapidus RG, Ferguson AT, Ottaviano YL, et al. Methylation of estrogen and progesterone receptor gene 5' CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. Clin Cancer Res 1996;2:805–10.[Abstract]
  10. Lapidus RG, Nass SJ, Butash KA, et al. Mapping of ER gene CpG island methylation-specific polymerase chain reaction. Cancer Res 1998;58:2515–9.[Abstract/Free Full Text]
  11. Iwase H, Omoto Y, Iwata H, et al. DNA methylation analysis at distal and proximal promoter regions of the oestrogen receptor gene in breast cancers. Br J Cancer 1999;80:1982–6.[CrossRef][Medline]
  12. Ferguson AT, Lapidus RG, Davidson NE. Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression. Oncogene 1998;17:577–83.[CrossRef][Medline]
  13. Cooper AJL. Biochemistry of sulfur-containing amino acids. Annu Rev Biochem 1983;52:187–222.[CrossRef][Medline]
  14. Mason JB, Levesque T. Folate: effects on carcinogenesis and the potential for cancer chemoprevention. Oncology 1996;10:1727–36; 1742–3.[Medline]
  15. Zhu K, Williams SM. Methyl-deficient diets, methylated ER genes and breast cancer: an hypothesized association. Cancer Causes Control 1998;9:615–20.[CrossRef][Medline]
  16. Ames BN. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res 2001;475:7–20.[Medline]
  17. Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 1997;94:3290–5.[Abstract/Free Full Text]
  18. Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281:1632–7.[Abstract/Free Full Text]
  19. Zhang SM, Willett WC, Selhub J, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 2003;95:373–80.[Abstract/Free Full Text]
  20. Rohan TE, Jain MG, Howe GR, Miller AB. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:266–9.[Free Full Text]
  21. Sellers TA, Kushi LH, Cerhan JR, et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 2001;12:420–8.[CrossRef][Medline]
  22. Negri E, La Vecchia C, Franceschi S. Re: dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:1270–1.[Free Full Text]
  23. Ronco A, De Stefani E, Boffetta P, Deneo-Pellegrini H, Mendilaharsu M, Leborgne F. Vegetables, fruits, and related nutrients and risk of breast cancer: a case-control study in Uruguay. Nutr Cancer 1999;35:111–9.[CrossRef][Medline]
  24. Freudenheim JL, Marshall JR, Vena JE, et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst 1996;88:340–8.[Abstract/Free Full Text]
  25. Graham S, Hellmann R, Marshall J, et al. Nutritional epidemiology of postmenopausal breast cancer in Western New York. Am J Epidemiol 1991;134:552–66.[Abstract/Free Full Text]
  26. Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer 2001;91:260–3.[CrossRef][Medline]
  27. Shrubsole MJ, Jin F, Dai Q, et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 2001;61:7136–41.[Abstract/Free Full Text]
  28. Hillman RS, Steinberg SE. The effects of alcohol on folate metabolism. Annu Rev Med 1982;33:345–54.[CrossRef][Medline]
  29. Weir DG, McGing PG, Scott JM. Folate metabolism, the enterohepatic circulation and alcohol. Biochem Pharmacol 1985;34:1–7.[CrossRef][Medline]
  30. Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:51–65.[Abstract/Free Full Text]
  31. Willett WC, Sampson L, Browne ML, et al. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol 1988;127:188–99.[Abstract/Free Full Text]
  32. Salvini S, Hunter DJ, Sampson L, et al. Food-based validation of a dietary questionnaire: the effects of week-to-week variation in food consumption. Int J Epidemiol 1989;18:858–67.[Abstract/Free Full Text]
  33. Willett WC. Nutritional epidemiology. New York: Oxford University Press; 1998.
  34. Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875–84.[Abstract/Free Full Text]
  35. Giovannucci E, Colditz G, Stampfer MJ, et al. The assessment of alcohol consumption by a simple self-administered questionnaire. Am J Epidemiol 1991;133:810–7.[Abstract/Free Full Text]
  36. Stampfer MJ, Willett WC, Speizer FE, et al. Test of the National Death Index. Am J Epidemiol 1984;119:837–9.[Free Full Text]
  37. Hu FB, Stampfer MJ, Rimm E, et al. Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol 1999;149:531–40.[Abstract/Free Full Text]
  38. Rothman KJ. Modern epidemiology. Boston (MA): Little, Brown and Company; 1986.
  39. Cupples LA, D'Agostino RB, Anderson K, Kannel WB. Comparison of baseline and repeated measure covariate techniques in the Framingham Heart Study. Stat Med 1988;7:205–18.[Medline]
  40. D'Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. Stat Med 1990;9:1501–15.[Medline]
  41. Lopatina NG, Vanyushin BF, Cronin GM, Poirier LA. Elevated expression and altered pattern of activity of DNA methyltransferase in liver tumors of rats fed methyl-deficient diets. Carcinogenesis 1998;19:1777–81.[Abstract/Free Full Text]
  42. Pogribny IP, James SJ, Jernigan S, Pogribna M. Genomic hypomethylation is specific for preneoplastic liver in folate/methyl deficient rats and does not occur in non-target tissues. Mutat Res 2004;548:53–9.[Medline]
  43. Zhu K, Davidson NE, Hunter S, et al. Methyl-group dietary intake and risk of breast cancer among African-American women: a case-control study by methylation status of the estrogen receptor {alpha} genes. Cancer Causes Control 2003;14:827–36.[CrossRef][Medline]
  44. Gregory JF III. Case study: folate bioavailability. J Nutr 2001;131:1376–82S.
  45. Feigelson HS, Jonas CR, Robertson AS, McCullough ML, Thun MJ, Calle EE. Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2003;12:161–4.[Abstract/Free Full Text]
  46. Hidiroglou N, Camilo ME, Beckenhauer HC, et al. Effect of chronic alcohol ingestion on hepatic folate distribution in the rat. Biochem Pharmacol 1994;47:1561–6.[CrossRef][Medline]
  47. Barak AJ, Beckenhauer HC, Hidiroglou N, Camilo ME, Selhub J, Tuma DJ. The relationship of ethanol feeding to the methyl folate trap. Alcohol 1993;10:495–7.[CrossRef][Medline]
  48. Shaw S, Jayatilleke E, Herbert V, Colman N. Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide. Biochem J 1989;257:277–80.[Medline]
  49. Guynn RW, Labaume LB, Henkin J. Equilibrium constants under physiological conditions for the condensation of acetaldehyde with tetrahydrofolic acid. Arch Biochem Biophys 1982;217:181–90.[CrossRef][Medline]
  50. Sellers TA, Vierkant RA, Cerhan JR, et al. Interaction of dietary folate intake, alcohol, and risk of hormone receptor-defined breast cancer in a prospective study of postmenopausal women. Cancer Epidemiol Biomarkers Prev 2002;11:1104–7.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am J EpidemiolHome page
K. Ishitani, J. Lin, J. E. Manson, J. E. Buring, and S. M. Zhang
A Prospective Study of Multivitamin Supplement Use and Risk of Breast Cancer
Am. J. Epidemiol., May 15, 2008; 167(10): 1197 - 1206.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
M. Lajous, M.-C. Boutron-Ruault, A. Fabre, F. Clavel-Chapelon, and I. Romieu
Carbohydrate intake, glycemic index, glycemic load, and risk of postmenopausal breast cancer in a prospective study of French women
Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1384 - 1391.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
J. Lin, I-M. Lee, N. R Cook, J. Selhub, J. E Manson, J. E Buring, and S. M Zhang
Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women
Am. J. Clinical Nutrition, March 1, 2008; 87(3): 734 - 743.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
E. Cho, M. Holmes, S. E. Hankinson, and W. C. Willett
Nutrients Involved in One-Carbon Metabolism and Risk of Breast Cancer among Premenopausal Women
Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2787 - 2790.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
S. C. Larsson, E. Giovannucci, and A. Wolk
Folate and Risk of Breast Cancer: A Meta-analysis
J Natl Cancer Inst, January 3, 2007; 99(1): 64 - 76.
[Abstract] [Full Text] [PDF]

Home page
 Arch Intern MedHome page
A. Bardia, L. C. Hartmann, C. M. Vachon, R. A. Vierkant, A. H. Wang, J. E. Olson, T. A. Sellers, and J. R. Cerhan
Recreational Physical Activity and Risk of Postmenopausal Breast Cancer Based on Hormone Receptor Status
Arch Intern Med, December 11, 2006; 166(22): 2478 - 2483.
[Abstract] [Full Text] [PDF]

Home page
 Am J EpidemiolHome page
S. S. Tworoger, J. L. Hecht, E. Giovannucci, and S. E. Hankinson
Intake of Folate and Related Nutrients in Relation to Risk of Epithelial Ovarian Cancer
Am. J. Epidemiol., June 15, 2006; 163(12): 1101 - 1111.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
R. Z Stolzenberg-Solomon, S.-C. Chang, M. F Leitzmann, K. A Johnson, C. Johnson, S. S Buys, R. N Hoover, and R. G Ziegler
Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
Am. J. Clinical Nutrition, April 1, 2006; 83(4): 895 - 904.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, S. M.
Right arrow Articles by Willett, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, S. M.
Right arrow Articles by Willett, W. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online