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High intakes of choline and betaine reduce breast cancer mortality in a population-based study

Xinran Xu^*, Marilie D. Gammon^¶, Steven H. Zeisel^#, Patrick T. Bradshaw^¶, James G. Wetmur^,, Susan L. Teitelbaum^*, Alfred I. Neugut^**,, Regina M. Santella and Jia Chen^*,,||,1

^* Department of Community and Preventive Medicine,

Department of Microbiology,

Department of Genetics and Genomic Sciences,

Department of Pediatrics, and

^|| Department of Oncological Science, Mount Sinai School of Medicine, New York, New York, USA;

^¶ Department of Epidemiology and

^# Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA; and

^** Department of Epidemiology,

Department of Medicine, and

Department of Environmental Health Sciences, Columbia University, New York, New York, USA

¹ Correspondence: Department of Community and Preventive Medicine, Box 1057, Mt. Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. E-mail: jia.chen{at}mssm.edu

Choline and betaine provide methyl groups for one-carbon metabolism. Humans obtain these nutrients from a wide range of foods. Betaine can also be synthesized endogenously from its precursor, choline. Although animal studies have implied a causal relationship between choline deficiency and carcinogenesis, the role of these two nutrients in human carcinogenesis and tumor progression is not well understood. We investigated the associations of dietary intakes of choline and betaine and breast cancer risk and mortality in the population-based Long Island Breast Cancer Study Project. Among the 1508 case-group women, 308 (20.2%) deaths occurred, among whom 164 (53.2%) died of breast cancer by December 31, 2005. There was an indication that a higher intake of free choline was associated with reduced risk of breast cancer (P_trend=0.04). Higher intakes of betaine, phosphocholine, and free choline were associated with reduced all-cause as well as breast cancer-specific mortality in a dose-dependent fashion. We also explored associations of polymorphisms of three key choline- and betaine-metabolizing genes and breast cancer mortality. The betaine-homocysteine methyltransferase gene (BHMT) rs3733890 polymorphism was associated with reduced breast cancer-specific mortality (hazard ratio, 0.64; 95% confidence interval, 0.42–0.97). Our study supports the important roles of choline and betaine in breast carcinogenesis. It suggests that high intake of these nutrients may be a promising strategy to prevent the development of breast cancer and to reduce its mortality.—Xu, X., Gammon, M. D., Zeisal, S. H., Bradshaw, P. T., Wetmur, J. G., Teitelbaum, S. L., Neugut, A. I., Santella, R. M., Chen, J. High intakes of choline and betaine reduce breast cancer mortality in a population-based study.

Key Words: risk • diet • BHMT • LIBCSP