Folate, DNA methylation, and mouse models of breast tumorigenesis.

摘要: Since the late 1990s, food supply of United States, Canada, and other countries has been fortified with folic acid to lower incidence neural tube defects (e.g., spina bifida, anencephaly). This fortification program highly successful in reducing both prevalence folate deficiency general population1,2 defects.3 The success program, however, created a situation excess consumption by significant percentage population, negative ramifications which, if any, are as yet undetermined. Geometric mean serum levels have more than doubled US population (from ∼12 ∼30 nmol/L)4 supplement users intakes above upper tolerable intake level (>1 mg acid/day) increased from ∼1% ∼11%.5 Because anti-folate drugs known retard or prevent proliferation tumors, some raised question whether may promote malignant progression.6 Indeed, recent analysis data U.S. Canada suggests that colorectal cancer much 10%.7 Most cancers develop through series stages transformations normal neoplasia situ, invasive carcinoma, ultimately metastasis. Folate is potentially an important mediator progressive changes tumor cell biology, based on its central role one-carbon metabolism (Figure 1). Folate, form 5,10-methylenetetrahydrofolate, three major biochemical fates. First, it serves donor conversion deoxyuridine thymidylate, which turn incorporated into DNA. causes inhibition this reaction, can result uracil misincorporation DNA.8 DNA …