Effects of Folate Deficiency and Supplementation on Methylnitrosourea-Induced Rat Mammary Tumors

Baggott, Joseph E.; Vaughn, William H.; Juliana, M. Margaret; Eto, Isao; Krumdieck, Carlos L.; Grubbs, Clinton J.

doi:10.1093/jnci/84.22.1740

Cited by 78 publications

(47 citation statements)

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“…One potential harmful consequence of folate fortification is the risk of modification on DNA methylation (10). In some animal studies, dietary folate deficiency can inhibit rather than enhance the development of breast cancer in rats (43,44), which is in contrast to the observation in epidemiologic studies. It suggested that folate possesses dual effects on carcinogenesis depending on the time and dose of folate intake.…”

Section: Discussionmentioning

confidence: 91%

Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in Esophageal Squamous Cell Carcinoma

Wang

Sasco²,

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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To explore the role of aberrant hypermethylation of cancer-related genes, such as P16, MGMT, and hMLH1, in the esophageal squamous cell carcinoma (ESCC) as well as its relation to dietary folate intake and MTHFR C677T polymorphism, we conducted a molecular epidemiologic study in China. One hundred and twentyfive histologically confirmed ESCC patients having undergone surgery in the Yangzhong People's Hospital between January 2005 and March 2006 were recruited. The aberrant CpG island hypermethylation of P16, MGMT, and hMLH1 genes could be found in cancer tissues with frequency of about 88.0%, 27.2%, and 3.2%, respectively, and in remote normal-appearing esophageal tissues with frequency of about 36.8%, 11.2%, and 0.0%, respectively. No hypermethylation was found in the normal esophageal tissues from healthy controls. Compared with those patients without lymph node metastasis, MGMT gene showed a higher proportion of hypermethylation in cancer tissues, whereas P16 gene showed a higher proportion of hypermethylation in remote normal-appearing esophageal tissues in patients with lymph node metastasis. A significant association was found between MTHFR C677T genetic polymorphism and CpG island methylation status of MGMT gene. After adjustment for potential confounders, individuals carrying CT or TT genotype have higher frequency of hypermethylation in MGMT gene in cancer tissues, with odds ratio of 3.34 (95% confidence interval, 1.07-10.39) and 3.83 (95% confidence interval, 1.13-12.94), respectively. This study indicated that the aberrant CpG island hypermethylation of cancerrelated genes was associated with ESCC and might be a promising biomarker in diagnosis and prognosis.

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Section: Discussionmentioning

confidence: 91%

Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in Esophageal Squamous Cell Carcinoma

Wang

Sasco²,

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Furthermore, promotion of in-stent restenosis after high dose folic acid has been observed (Lange et al, 2004). It was recently suggested that high dose folic acid might promote DNA hypomethylation and tumor growth (Baggott et al, 1992;Bills et al, 1992). These results highlight the necessity of determining the maximum tolerable dose of folic acid, taking into consideration effects on liver function.…”

Section: Discussionmentioning

confidence: 97%

Effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma total homocysteine concentrations in young Japanese male subjects

et al. 2005

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Objective: To investigate the effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma plasma total homocysteine (tHcy) concentrations in young Japanese male subjects. Design: In a double blind, randomized controlled trial. Intervention: Subjects were randomly assigned to one of four groups and received a placebo (control group), 800 mg/day folic acid (FA group), 8.4 mg/day riboflavin (R group), or both (FAR group) for 2 weeks. Setting: Tokyo, Japan. Subjects: In total, 32 healthy male volunteers aged 20-29 years. Results: At the end of the 2 week supplementation period, the tHcy concentration decreased significantly in the FA group. Serum folate concentrations had increased between 2.7 and 2.0-fold in the FA and FAR groups, respectively, but the mean within-group changes in serum folate and plasma tHcy concentrations did not differ between these two groups. At the end of the study, alanine amino transferase was decreased in the R and FAR groups, while alanine amino transferase was increased in the FA group. Conclusion: Supplementation with folic acid, 800 mg/day, for 2 weeks, increased the serum and red blood cell folate concentrations and decreased the plasma tHcy concentrations in healthy young male subjects. Riboflavin supplementation may have blunted the effect of folic acid, which resulted in a diminished reduction of tHcy in our subjects.

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“…Previous animal studies conducted in another chemical carcinogen rat model collectively suggest that mild dietary folate deficiency inhibits, whereas folic acid supplementation (4-20Â BDR) does not modulate, the development and progression of mammary tumors (25,26,38). In these studies, dietary folic acid supplementation was initiated only at weaning (25,26,38), suggesting that in utero supplementation has a drastically different effect on mammary tumor risk.…”

Section: Discussionmentioning

confidence: 98%

“…In these studies, dietary folic acid supplementation was initiated only at weaning (25,26,38), suggesting that in utero supplementation has a drastically different effect on mammary tumor risk. In contrast to the present study, we have previously reported that maternal folic acid supplementation provided in utero and during lactation significantly reduced the number of terminal end buds of the mammary glands at puberty, a purported biomarker of mammary tumor risk in rodents (23,24), in the offspring (39).…”

Section: Discussionmentioning

confidence: 99%

Effect of Maternal and Postweaning Folic Acid Supplementation on Mammary Tumor Risk in the Offspring

et al. 2011

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Intrauterine and early life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use, and periconceptional supplementation. We investigated the effects of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Female rats were placed on a control or folic acid-supplemented diet prior to mating and during pregnancy and lactation. At weaning, female pups from each maternal diet group were randomized to the control or supplemented diet and mammary tumors were induced with 7,12 dimethylbenz[a]anthracene at puberty. At necropsy, mammary tumor parameters, genomic DNA methylation, and DNA methyltransferase activity were determined in the offspring. Both maternal and postweaning folic acid supplementation significantly increased the risk of mammary adenocarcinomas in the offspring (OR ¼ 2.1, 95% CI 1.2-3.8, P ¼ 0.008 and OR ¼ 1.9, 95% CI 1.1-3.3, P ¼ 0.03, respectively). Maternal folic acid supplementation also significantly accelerated the rate of mammary adenocarcinoma appearance (P ¼ 0.002) and increased the multiplicity of mammary adenocarcinomas (P ¼ 0.008) in the offspring. Maternal, but not postweaning, folic acid supplementation significantly reduced global DNA methylation (P ¼ 0.03), whereas postweaning, but not maternal, folic acid supplementation significantly decreased DNA methyltransferase activity (P ¼ 0.05) in nonneoplastic mammary glands of the offspring. Our findings suggest that a high intrauterine and postweaning dietary exposure to folic acid may increase the risk of mammary tumors in the offspring. Further, they suggest that this tumor-promoting effect may be mediated in part by altered DNA methylation and DNMT activity. Cancer Res; 71(3); 988-97. Ó2010 AACR.

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Effects of Folate Deficiency and Supplementation on Methylnitrosourea-Induced Rat Mammary Tumors

Abstract: Since the rat is relatively resistant to folate deficiency anemia, other animal models should be used to test the effect of folate nutriture on carcinogenesis.

Cited by 78 publications

References 0 publications

Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in Esophageal Squamous Cell Carcinoma

Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in Esophageal Squamous Cell Carcinoma

Effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma total homocysteine concentrations in young Japanese male subjects

Effect of Maternal and Postweaning Folic Acid Supplementation on Mammary Tumor Risk in the Offspring

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