Homocysteine (Hcy) is an intermediary product in methionine metabolism and an elevation in plasma Hcy is a sensitive biomarker for an imbalance in the integrated pathways of one-carbon metabolism. More recently, there has been interest in the potential links between total Hcy, folate and cancer. In this study, the association of plasma Hcy levels with the breast cancer risk was investigated. Questionnaire information and blood samples were taken before treatment from 146 women with newly diagnosed, histologically confirmed breast cancer and 285 age-matched control women who were admitted for health examination. Plasma levels of Hcy and folate were measured by enzyme conversion immunoassay and radioassay, respectively. Dietary intake of B-group vitamins was estimated using a semi-quantitative dietary questionnaire. Logistic regression was used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Elevated plasma Hcy levels were significantly linked to increased risk of breast cancer (adjusted OR = 2.89, 95% CI = 1.70-4.92 for the highest tertile as compared with the lowest tertile). Moreover, a similar pattern of enhanced breast cancer risk at higher plasma Hcy levels was observed in both pre-menopausal and post-menopausal women. And this consistent pattern did not differ substantially by level of dietary intake of B-group vitamins. The current study results seem to suggest a possibility that the plasma Hcy levels could be a metabolic risk factor for breast cancer. Future studies are needed to prove causality and provide insight on the mechanism of action of Hcy in breast tumorigenesis.
[Show abstract][Hide abstract] ABSTRACT: Epidemiologic findings are inconsistent concerning risk for breast cancer associated with low folate intake or blood folate levels. We performed a meta-analysis of prospective and case-control studies to examine folate intake and levels in relation to risk of breast cancer.
We searched MEDLINE for studies of this association that were published in any language from January 1, 1966, through November 1, 2006. Study-specific risk estimates were pooled by use of a random-effects model. All statistical tests were two-sided.
Folate intake in increments of 200 microg/day was not associated with the risk of breast cancer in prospective studies (estimated summary relative risk [RR] = 0.97, 95% confidence interval [CI] = 0.88 to 1.07, for dietary folate [eight studies; 302,959 participants and 8367 patients with breast cancer], and RR = 1.01, 95% CI = 0.97 to 1.05, for total folate [six studies; 306,209 participants and 8165 patients with breast cancer]) but was statistically significantly inversely associated with risk in case-control studies (estimated summary odds ratio [OR] = 0.80, 95% CI = 0.72 to 0.89, for dietary folate [13 studies; 8558 case patients and 10,812 control subjects], and OR = 0.93, 95% CI = 0.81 to 1.07, for total folate [three studies; 2184 case patients and 3233 control subjects]). High blood folate levels versus low levels were not statistically significantly associated with the risk of breast cancer in prospective studies (OR = 0.81, 95% CI = 0.59 to 1.10 [three studies]) or in case-control studies (OR = 0.41, 95% CI = 0.15 to 1.10 [two studies]). Among the two prospective studies and two case-control studies that stratified by alcohol consumption, high folate intake (comparing the highest with the lowest category) was associated with a statistically significant decreased risk of breast cancer among women with moderate or high alcohol consumption (summary estimate = 0.51, 95% CI = 0.41 to 0.63) but not among women with low or no alcohol consumption (summary estimate = 0.95, 95% CI = 0.78 to 1.15). Few studies examined whether the relation between folate intake and breast cancer was modified by intakes of methionine or vitamins B6 and B12, and the findings were inconsistent.
No clear support for an overall relationship between folate intake or blood folate levels and breast cancer risk was found. Adequate folate intake may reduce the increased risk of breast cancer that has been associated with moderate or high alcohol consumption.
Journal of the National Cancer Institute 02/2007; 99(1):64-76. DOI:10.1093/jnci/djk006 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The interconversion of folates by the one-carbon metabolism pathway is essential for the synthesis of precursors used in DNA synthesis, repair, and methylation. Perturbations in this pathway can disrupt these processes and are hypothesized to facilitate carcinogenesis. We investigated associations of 25 candidate polymorphisms in nine one-carbon metabolism genes with risk of postmenopausal breast cancer using 502 cases and 505 controls from the Cancer Prevention II Nutrition Cohort. Four single nucleotide polymorphisms (SNP) in three different genes were significantly associated with breast cancer. The nonsynonymous R134K SNP in methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthase [MTHFD1; odds ratio (OR), 1.40; 95% confidence interval (95% CI), 1.06-1.85 for CT + TT] and an intronic SNP in formyltetrahydrofolate dehydrogenase (FTHFD; OR, 2.23; 95% CI, 1.09-4.54 for CC) were associated with a significant increase in risk. Significantly decreased risk was associated with an intronic SNP in FTHFD (OR, 0.75; 95% CI, 0.58-0.98 for CT + CC) and the A360A SNP in cystathionine beta-synthase (CBS; OR, 0.63; 95% CI, 0.41-0.96 for TT). The presence of at least one variant from both the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C SNPs was also associated with increased risk (OR, 2.16; 95% CI, 1.34-3.48 for 677 CT + TT/1,298 AC + CC). Investigations into interactions of the associated SNPs with each other and with dietary factors yielded inconclusive results. Our findings indicate that genetic variation in multiple one-carbon metabolism genes may influence risk of postmenopausal breast cancer and may involve changes in methyl donor synthesis. However, larger studies are needed to further examine gene/gene and gene/diet interactions in this pathway.
[Show abstract][Hide abstract] ABSTRACT: Methionine synthase (MS) is a cobalamin-dependent enzyme. It transfers a methyl group from methyltetrahydrofolate to homocysteine forming methionine and tetrahydrofolate. On the basis of sequence similarity with Escherichia coli cobalamin-dependent MS (MetH), human MS comprises four discrete functional modules that bind from the N- to C-terminus, respectively, homocysteine, methyltetrahydrofolate, cobalamin, and S-adenosylmethionine (AdoMet). The C-terminal activation domain also interacts with methionine synthase reductase (MSR), a NADPH-dependent diflavin oxidoreductase required for the reductive regeneration of catalytically inert cob(II)alamin (which is formed every 200-1000 catalytic cycles of MS) to cob(I)alamin. We have investigated complex formation between the (i) MS activation domain and MSR and (ii) MS activation domain and the isolated FMN-binding domain of MSR. We show that the MS activation domain interacts directly with the FMN-binding domain of MSR. Binding is weakened at high ionic strength, emphasizing the importance of electrostatic interactions at the protein-protein interface. Mutagenesis of conserved lysine residues (Lys1071 and Lys987) in the human activation domain weakens this protein interaction. Chemical cross-linking demonstrates complex formation mediated by acidic residues (FMN-binding domain) and basic residues (activation domain). The activation domain and isolated FMN-domain form a 1:1 complex, but a 1:2 complex is formed with activation domain and MSR. The midpoint reduction potentials of the FAD and FMN cofactors of MSR are not perturbed significantly on forming this complex, implying that electron transfer to cob(II)alamin is endergonic. The kinetics of electron transfer in MSR and the MSR-activation domain complex are similar. Our studies indicate (i) conserved binding determinants, but differences in protein stoichiometry, between human MS and bacterial MetH in complex formation with redox partners; (ii) a substantial endergonic barrier to electron transfer in the reactivation complex; and (iii) a lack of control on the thermodynamics and kinetics of electron transfer in MSR exerted by complex formation with activation domain. The structural and functional consequences of complex formation are discussed in light of the known crystal structure of human activation domain and the inferred conformational heterogeneity of the multidomain MSR-MS complex.
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