B-vitamin intake, one-carbon metabolism, and survival in a population-based study of women with breast cancer

Abstract

Breast cancer is the second leading cause of cancer mortality among women. Given its important role in DNA methylation and synthesis, one-carbon metabolism may affect breast cancer mortality. We used a population-based cohort of 1,508 women with breast cancer to investigate possible associations of dietary intake of B vitamins before diagnosis as well as nine polymorphisms of one-carbon metabolizing genes and subsequent survival. Women newly diagnosed with a first primary breast cancer in 1996 to 1997 were followed for vital status for an average of 5.6 years. Kaplan-Meier survival and Cox proportional hazard regression analyses were used to evaluate the association between dietary intakes of B vitamins (1,479 cases), genotypes ( approximately 1,065 cases), and all-cause as well as breast cancer-specific mortality. We found that higher dietary intake of vitamin B(1) and B(3) was associated with improved survival during the follow-up period (P(trend) = 0.01 and 0.04, respectively). Compared with the major genotype, the MTHFR 677 T allele carriers have reduced all-cause mortality and breast cancer-specific mortality in a dominant model [hazard ratio (95% confidence interval): 0.69 (0.49-0.98) and 0.58 (0.38-0.89), respectively]. The BHMT 742 A allele was also associated with reduced all-cause mortality [hazard ratio, 0.70 (0.50-1.00)]. Estrogen receptor/progesterone receptor status modified the association between the MTHFR C677T polymorphism and survival (P = 0.05). The survival associations with one-carbon polymorphisms did not differ with the use of chemotherapy, although study power was limited for examining such effect modification. Our results indicate that one-carbon metabolism may be an important pathway that could be targeted to improve breast cancer survival.

Figure 1

Schematic illustration of one-carbon metabolism pathway. Key genes involved in one-carbon metabolism include methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TYMS), methionine synthase (MTR), methionine synthase reductase (MTRR), cytosol serine hydroxymethyltransferase (cSHMT), dihydrofolate reductase (DHFR), and betaine-homocysteine methyltransferase (BHMT). Reduced folate carrier (RFC1) and human folate receptor (hFR) transport the dietary polyglutamyl folate (the predominant form of folate in diet) in intestinal absorption. B vitamins are co-factors of one-carbon enzymes as shown. Chemotherapy drugs 5-fluorouracil (5-FU) targets TYMS and methotrexate targets DHFR to block DNA synthesis. Hcy, homocysteine; SAM, S-adenosylmethionine; SAH, adenosylhomocysteine; THF, tetrahydrofolate; DHF, dihydrofolate; dUMP, deoxyuridine monophosphate; dUTP, deoxythymidine monophosphate.