EPIDEMIOLOGY Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer Joanne Kotsopoulos Æ William W. Zhang Æ Shiyu Zhang Æ David McCready Æ Maureen Trudeau Æ Phil Zhang Æ Ping Sun Æ Steven A. Narod Received: 3 January 2008 / Accepted: 4 January 2008 / Published online: 19 January 2008 Ó Springer Science+Business Media, LLC. 2008 Abstract Background An accumulating body of evidence suggests that there is an inverse relationship between the intake of folate (a water-soluble B-vitamin) and the risk of developing breast cancer. Individual variation in the genes involved in the transport of folate, or its metabolism, may affect risk, or may modify the association between folate and breast cancer risk. Methods We performed a case- control study to evaluate the association between common polymorphisms in six folate-related genes and the risk of breast cancer in 1,009 breast cancer patients and 907 healthy controls. Study subjects were genotyped for eight single nucleotide polymorphisms (SNPs) in these six genes. Results We observed no association between the MTHFR, RFC, MS and MTRR genotypes and the risk of breast cancer. Conclusion These data do not support the hypothesis that genetic variation in genes involved in the metabolism of folate are implicated in the etiology of breast cancer. Keywords Folate Á Breast cancer Á Single nucleotide polymorphisms Introduction Folate, a water-soluble B-vitamin, is as an important nutritional factor which may have a role as a cancer-pre- venting agent [1]. The principal biochemical role of folate in mammals is in mediating the transfer of single-carbon molecules for various biological reactions [2]. Folate plays an integral role in DNA synthesis and methylation, and as an epigenetic regulator of gene expression, DNA integrity and stability [1, 2]. Folate in the intracellular coenzymatic form (5, 10-methylenetetrahydrofolate) is required for de novo purine and thymidylate synthesis [2]. In the form of 5-methyltetrahydrofolate, folate is involved in the reme- thylation of homocysteine to methionine, the precursor of S-adenoysylmethionine and is the primary methyl group donor for most biological methylation reactions, including that of DNA [3]. Folate deficiency due to low dietary or supplemental intake, or impaired absorption or metabo- lism, may result in increased numbers of DNA strand breaks, impaired DNA repair, enhanced mutagenesis and alterations in DNA methylation patterns. All of these events have been implicated in neoplastic transformation [4–7]. The evidence is strong for an inverse association between folate status and the risk of colorectal cancer [7], and there is also an accumulating body of epidemiologic evidence which suggests that the vitamin is also implicated in breast cancer (reviewed in [8]), although, the evidence is conflicting [9, 10]. Studies have evaluated a role of dietary or circulating folate levels and the risk of breast cancer, these include multivitamin or supplement use, blood levels J. Kotsopoulos Á W. W. Zhang Á S. Zhang Á P. Zhang Á P. Sun Á S. A. Narod (&) Women’s College Research Institute, Women’s College Hospital, University of Toronto, 790 Bay Street, 7th Floor, Room 750, Toronto, Canada M5G 1N8 e-mail: steven.narod@wchospital.ca J. Kotsopoulos Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada D. McCready Surgical Oncology, University Health Network, Toronto, ON, Canada M. Trudeau Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada 123 Breast Cancer Res Treat (2008) 112:585–593 DOI 10.1007/s10549-008-9895-6