This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (184)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in JAMA  Topic Collections  • Oncology  • Breast Cancer  • Alert me on articles by topic

Shumin Zhang, MD, ScD; David J. Hunter, MBBS, ScD; Susan E. Hankinson, ScD; Edward L. Giovannucci, MD, ScD; Bernard A. Rosner, PhD; Graham A. Colditz, MD, DrPH; Frank E. Speizer, MD; Walter C. Willett, MD, DrPH

JAMA. 1999;281:1632-1637.

Context  Folate is involved in DNA synthesis and methylation and may reduce breast cancer risk, particularly among women with greater alcohol consumption.

Objectives  To assess the association between folate intake and risk of breast cancer and whether higher folate intake may reduce excess risk among women who consume alcohol.

Design  Prospective cohort study performed in 1980, with 16 years of follow-up.

Setting and Participants  A total of 88,818 women who completed the dietary questionnaire section of the Nurses' Health Study in 1980.

Main Outcome Measure  Incidence of invasive breast cancer by levels of folate and alcohol intake.

Results  A total of 3483 cases of breast cancer were documented. Total folate intake was not associated with overall risk of breast cancer. However, among women who consumed at least 15 g/d of alcohol, the risk of breast cancer was highest among those with low folate intake. For total folate intake of at least 600 µg/d compared with 150 to 299 µg/d, the multivariate relative risk (RR) was 0.55 (95% confidence interval [CI], 0.39-0.76; P for trend=.001). This association was only slightly attenuated after additional adjustment for intake of beta carotene, lutein/zeaxanthin, preformed vitamin A, and total vitamins C and E. The risk of breast cancer associated with alcohol intake was strongest among women with total folate intake of less than 300 µg/d (for alcohol intake 15 g/d vs <15 g/d, multivariate RR, 1.32; 95% CI, 1.15-1.50). For women who consumed at least 300 µg/d of total folate, the multivariate RR for intake of at least 15 g/d of alcohol vs less than 15 g/d was 1.05 (95% CI, 0.92-1.20). Current use of multivitamin supplements, the major source of folate, was associated with lower breast cancer risk among women who consumed at least 15 g/d of alcohol (for current users of supplements vs never users, RR, 0.74; 95% CI, 0.59-0.93).

Conclusions  Our findings suggest that the excess risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake.

Author Affiliations: Departments of Epidemiology (Drs Zhang, Hunter, Hankinson, Colditz, and Willett) and Nutrition (Drs Zhang, Giovannucci, and Willett), Harvard Center for Cancer Prevention (Drs Hunter and Colditz), Harvard School of Public Health, and the Channing Laboratory (Drs Hunter, Hankinson, Giovannucci, Rosner, Colditz, Speizer, and Willett), Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass.

RELATED ARTICLE

May 5, 1999
JAMA. 1999;281(17):1663-1664.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

The promise and challenges of population strategies of prevention
Michels
Int J Epidemiol 2008;37:914-916.
FULL TEXT  

Effect of Prediagnostic Alcohol Consumption on Survival after Breast Cancer in Young Women
Reding et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:1988-1996.
ABSTRACT | FULL TEXT  

A Prospective Study of Multivitamin Supplement Use and Risk of Breast Cancer
Ishitani et al.
Am J Epidemiol 2008;167:1197-1206.
ABSTRACT | FULL TEXT  

Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women
Lin et al.
Am. J. Clin. Nutr. 2008;87:734-743.
ABSTRACT | FULL TEXT  

One-carbon metabolism-related gene polymorphisms and risk of breast cancer
Suzuki et al.
Carcinogenesis 2008;29:356-362.
ABSTRACT | FULL TEXT  

Nutrients Involved in One-Carbon Metabolism and Risk of Breast Cancer among Premenopausal Women
Cho et al.
Cancer Epidemiol. Biomarkers Prev. 2007;16:2787-2790.
ABSTRACT | FULL TEXT  

High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort
Ericson et al.
Am. J. Clin. Nutr. 2007;86:434-443.
ABSTRACT | FULL TEXT  

Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study
Xu et al.
Carcinogenesis 2007;28:1504-1509.
ABSTRACT | FULL TEXT  

Association of Polymorphisms in One-Carbon Metabolism Genes and Postmenopausal Breast Cancer Incidence
Stevens et al.
Cancer Epidemiol. Biomarkers Prev. 2007;16:1140-1147.
ABSTRACT | FULL TEXT  

A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users
Xu et al.
Am. J. Clin. Nutr. 2007;85:1098-1102.
ABSTRACT | FULL TEXT  

Alcohol Consumption and Breast Cancer Risk in the Women's Health Study
Zhang et al.
Am J Epidemiol 2007;165:667-676.
ABSTRACT | FULL TEXT  

Folate and Risk of Breast Cancer: A Meta-analysis
Larsson et al.
JNCI J Natl Cancer Inst 2007;99:64-76.
ABSTRACT | FULL TEXT  

Meta-analyses of Observational and Genetic Association Studies of Folate Intakes or Levels and Breast Cancer Risk.
Lewis et al.
JNCI J Natl Cancer Inst 2006;98:1607-1622.
ABSTRACT | FULL TEXT  

Nutrition and Physical Activity During and After Cancer Treatment: An American Cancer Society Guide for Informed Choices
Doyle et al.
CA Cancer J Clin 2006;56:323-353.
ABSTRACT | FULL TEXT  

Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan
Chou et al.
Carcinogenesis 2006;27:2295-2300.
ABSTRACT | FULL TEXT  

Dietary factors of one-carbon metabolism and prostate cancer risk.
Weinstein et al.
Am. J. Clin. Nutr. 2006;84:929-935.
ABSTRACT | FULL TEXT  

American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention: Reducing the Risk of Cancer With Healthy Food Choices and Physical Activity
Kushi et al.
CA Cancer J Clin 2006;56:254-281.
ABSTRACT | FULL TEXT  

Intake of Folate and Related Nutrients in Relation to Risk of Epithelial Ovarian Cancer
Tworoger et al.
Am J Epidemiol 2006;163:1101-1111.
ABSTRACT | FULL TEXT  

Folate Nutrition and Prostate Cancer Incidence in a Large Cohort of US Men
Stevens et al.
Am J Epidemiol 2006;163:989-996.
ABSTRACT | FULL TEXT  

Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
Stolzenberg-Solomon et al.
Am. J. Clin. Nutr. 2006;83:895-904.
ABSTRACT | FULL TEXT  

Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men.
Larsson et al.
JNCI J Natl Cancer Inst 2006;98:407-413.
ABSTRACT | FULL TEXT  

A new proposed guidance system for beverage consumption in the United States
Popkin et al.
Am. J. Clin. Nutr. 2006;83:529-542.
ABSTRACT | FULL TEXT  

Folate, vitamin b6, and vitamin B12 intake and the risk of breast cancer among mexican women.
Lajous et al.
Cancer Epidemiol. Biomarkers Prev. 2006;15:443-448.
ABSTRACT | FULL TEXT  

Diet Quality Is Associated with the Risk of Estrogen Receptor-Negative Breast Cancer in Postmenopausal Women
Fung et al.
J. Nutr. 2006;136:466-472.
ABSTRACT | FULL TEXT  

One-Carbon Metabolism and Breast Cancer Risk: No Association of MTHFR, MTR, and TYMS Polymorphisms in the GENICA Study from Germany
Justenhoven et al.
Cancer Epidemiol. Biomarkers Prev. 2005;14:3015-3018.
FULL TEXT  

Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study
Baglietto et al.
BMJ 2005;331:807.
ABSTRACT | FULL TEXT  

Effects of dietary folate on the development and progression of mammary tumors in rats
Kotsopoulos et al.
Carcinogenesis 2005;26:1603-1612.
ABSTRACT | FULL TEXT  

Folate Intake and Risk of Breast Cancer Characterized by Hormone Receptor Status
Zhang et al.
Cancer Epidemiol. Biomarkers Prev. 2005;14:2004-2008.
ABSTRACT | FULL TEXT  

The Effect of Folate Fortification of Cereal-Grain Products on Blood Folate Status, Dietary Folate Intake, and Dietary Folate Sources among Adult Non-Supplement Users in the United States
Dietrich et al.
J. Am. Coll. Nutr. 2005;24:266-274.
ABSTRACT | FULL TEXT  

Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine
Chiuve et al.
Am. J. Clin. Nutr. 2005;82:155-162.
ABSTRACT | FULL TEXT  

The Genome Health Clinic and Genome Health Nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis
Fenech
Mutagenesis 2005;20:255-269.
ABSTRACT | FULL TEXT  

Modifiable Risk Factors Associated with Clearance of Type-Specific Cervical Human Papillomavirus Infections in a Cohort of University Students
Richardson et al.
Cancer Epidemiol. Biomarkers Prev. 2005;14:1149-1156.
ABSTRACT | FULL TEXT  

One-Carbon Metabolism, MTHFR Polymorphisms, and Risk of Breast Cancer
Chen et al.
Cancer Res. 2005;65:1606-1614.
ABSTRACT | FULL TEXT  

MTHFR Polymorphisms, Diet, HRT, and Breast Cancer Risk: The Multiethnic Cohort Study
Le Marchand et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:2071-2077.
ABSTRACT | FULL TEXT  

Folate Intake and Risk of Parkinson's Disease
Chen et al.
Am J Epidemiol 2004;160:368-375.
ABSTRACT | FULL TEXT  

A Prospective Study of Folate Intake and the Risk of Pancreatic Cancer in Men and Women
Skinner et al.
Am J Epidemiol 2004;160:248-258.
ABSTRACT | FULL TEXT  

No Association between MTHFR 677 C->T or 1298 A->C Polymorphisms and Endometrial Cancer Risk
Paynter et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:1088-1089.
FULL TEXT  

Diet and alcohol consumption in relation to p53 mutations in breast tumors
Freudenheim et al.
Carcinogenesis 2004;25:931-939.
ABSTRACT | FULL TEXT  

Enhancement of folates in plants through metabolic engineering
Hossain et al.
Proc. Natl. Acad. Sci. USA 2004;101:5158-5163.
ABSTRACT | FULL TEXT  

Interaction between Genetic Variations in DNA Repair Genes and Plasma Folate on Breast Cancer Risk
Han et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:520-524.
ABSTRACT | FULL TEXT  

Dietary Folate Intake and Incidence of Ovarian Cancer: The Swedish Mammography Cohort
Larsson et al.
JNCI J Natl Cancer Inst 2004;96:396-402.
ABSTRACT | FULL TEXT  

MTHFR Polymorphisms, Dietary Folate Intake, and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study
Shrubsole et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:190-196.
ABSTRACT | FULL TEXT  

Dietary Glycemic Load and Breast Cancer Risk in the Women's Health Study
Higginbotham et al.
Cancer Epidemiol. Biomarkers Prev. 2004;13:65-70.
ABSTRACT | FULL TEXT  

Folate, Methyl-Related Nutrients, Alcohol, and the MTHFR 677C->T Polymorphism Affect Cancer Risk: Intake Recommendations
Bailey
J. Nutr. 2003;133:3748S-3753.
ABSTRACT | FULL TEXT  

Joint Association of Alcohol and Folate Intake with Risk of Major Chronic Disease in Women
Jiang et al.
Am J Epidemiol 2003;158:760-771.
ABSTRACT | FULL TEXT  

Association between Low Dietary Folate Intake and Suboptimal Cellular DNA Repair Capacity
Wei et al.
Cancer Epidemiol. Biomarkers Prev. 2003;12:963-969.
ABSTRACT | FULL TEXT  

Complex Multivitamin Supplementation Improves Homocysteine and Resistance to LDL-C Oxidation
Earnest et al.
J. Am. Coll. Nutr. 2003;22:400-407.
ABSTRACT | FULL TEXT  

Nutrition and Physical Activity During and After Cancer Treatment: An American Cancer Society Guide for Informed Choices
Brown et al.
CA Cancer J Clin 2003;53:268-291.
ABSTRACT | FULL TEXT  

Premenopausal Intakes of Vitamins A, C, and E, Folate, and Carotenoids, and Risk of Breast Cancer
Cho et al.
Cancer Epidemiol. Biomarkers Prev. 2003;12:713-720.
ABSTRACT | FULL TEXT  

Behavioral Risk Factors in Breast Cancer: Can Risk Be Modified?
McTiernan
The Oncologist 2003;8:326-334.
ABSTRACT | FULL TEXT  

Folic Acid Supplements and Fortification Affect the Risk for Neural Tube Defects, Vascular Disease and Cancer: Evolving Science,
Bailey et al.
J. Nutr. 2003;133:1961S-1968.
ABSTRACT | FULL TEXT  

Dietary Supplement Use in the Context of Health Disparities: Cultural, Ethnic and Demographic Determinants of Use
Jasti et al.
J. Nutr. 2003;133:2010S-2013.
ABSTRACT | FULL TEXT  

Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats
Kotsopoulos et al.
Carcinogenesis 2003;24:937-944.
ABSTRACT | FULL TEXT  

5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview
Robien and Ulrich
Am J Epidemiol 2003;157:571-582.
ABSTRACT | FULL TEXT  

Plasma Folate, Vitamin B6, Vitamin B12, Homocysteine, and Risk of Breast Cancer
Zhang et al.
JNCI J Natl Cancer Inst 2003;95:373-380.
ABSTRACT | FULL TEXT  

Alcohol, Folate, Methionine, and Risk of Incident Breast Cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort
Feigelson et al.
Cancer Epidemiol. Biomarkers Prev. 2003;12:161-164.
ABSTRACT | FULL TEXT  

Folate: A Key to Optimizing Health and Reducing Disease Risk in the Elderly
Rampersaud et al.
J. Am. Coll. Nutr. 2003;22:1-8.
ABSTRACT | FULL TEXT  

Interaction of Dietary Folate Intake, Alcohol, and Risk of Hormone Receptor-defined Breast Cancer in a Prospective Study of Postmenopausal Women
Sellers et al.
Cancer Epidemiol. Biomarkers Prev. 2002;11:1104-1107.
ABSTRACT | FULL TEXT  

Vitamins for Chronic Disease Prevention in Adults: Scientific Review
Fairfield and Fletcher
JAMA 2002;287:3116-3126.
ABSTRACT | FULL TEXT  

Vitamin A Intake and Hip Fractures Among Postmenopausal Women
Feskanich et al.
JAMA 2002;287:47-54.
ABSTRACT | FULL TEXT  

Interventional study of high dose folic acid in gastric carcinogenesis in beagles
Xiao et al.
Gut 2002;50:61-64.
ABSTRACT | FULL TEXT  

What Vitamins Should I Be Taking, Doctor?
Willett and Stampfer
NEJM 2001;345:1819-1824.
FULL TEXT  

Alcohol and Breast Cancer: Review of Epidemiologic and Experimental Evidence and Potential Mechanisms
Singletary and Gapstur
JAMA 2001;286:2143-2151.
ABSTRACT | FULL TEXT  

Low-to-Moderate Alcohol Consumption and Breast Cancer Risk by Age 50 Years among Women in Germany
Kropp et al.
Am J Epidemiol 2001;154:624-634.
ABSTRACT | FULL TEXT  

Dietary Folate Intake and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study
Shrubsole et al.
Cancer Res. 2001;61:7136-7141.
ABSTRACT | FULL TEXT  

COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk
Goodman et al.
Carcinogenesis 2001;22:1661-1665.
ABSTRACT | FULL TEXT  

Diet, alcohol, and health: a story of connections, confounders, and cofactors
Klatsky
Am. J. Clin. Nutr. 2001;74:279-280.
FULL TEXT  

Dietary and Other Methyl-Group Availability Factors and Pancreatic Cancer Risk in a Cohort of Male Smokers
Stolzenberg-Solomon et al.
Am J Epidemiol 2001;153:680-687.
ABSTRACT | FULL TEXT  

Association of the B-Vitamins Pyridoxal 5'-Phosphate (B6), B12, and Folate with Lung Cancer Risk in Older Men
Hartman et al.
Am J Epidemiol 2001;153:688-693.
ABSTRACT | FULL TEXT  

Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use
Koehler et al.
Am. J. Clin. Nutr. 2001;73:628-637.
ABSTRACT | FULL TEXT  

Diet and Cancer: One View at the Start of the Millennium
Willett
Cancer Epidemiol. Biomarkers Prev. 2001;10:3-8.
ABSTRACT | FULL TEXT  

Searching Expressed Sequence Tag Databases: Discovery and Confirmation of a Common Polymorphism in the Thymidylate Synthase Gene
Ulrich et al.
Cancer Epidemiol. Biomarkers Prev. 2000;9:1381-1385.
ABSTRACT | FULL TEXT  

Diet and Cancer
Willett
The Oncologist 2000;5:393-404.
ABSTRACT | FULL TEXT  

Re: Dietary Folate Consumption and Breast Cancer Risk
Negri et al.
JNCI J Natl Cancer Inst 2000;92:1270a-1271a.
FULL TEXT  

Dietary Folate Consumption and Breast Cancer Risk
Rohan et al.
JNCI J Natl Cancer Inst 2000;92:266-269.
FULL TEXT  

Other Articles Noted
Evid. Based Nurs. 1999;2:105-112.
FULL TEXT  

Folate May Lessen Breast Cancer Risk from Alcohol
JWatch Psychiatry 1999;1999:16-16.
FULL TEXT  

Breast Cancer, Alcohol Consumption, and Folate
JWatch Women's Health 1999;1999:2-2.
FULL TEXT  

Folate May Lessen Breast Cancer Risk from Alcohol
JWatch General 1999;1999:5-5.
FULL TEXT