title: Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats.
abstract: Epidemiologic studies have suggested that dietary folate intake is inversely related to breast cancer risk. However, epidemiologic evidence has not been consistent nor has it provided unequivocal support for this purported inverse relationship. This study investigated the effect of dietary folate on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis in rats. Weanling, female Sprague-Dawley rats were fed diets containing either 0 (deficient; n = 22), 2 (basal dietary requirement, control; n = 20) or 8 mg (supplemented; n = 20) folate/kg diet for 30 weeks. At 50 days of age, rats received an i.p. injection of MNU (50 mg/kg body wt). At necropsy, all macroscopic mammary tumors were identified and examined microscopically. The effect of dietary folate on genomic DNA methylation in mammary tumorigenesis was determined by the in vitro methyl acceptance assay. The incidence of mammary adenoma and adenocarcinoma in the folate-deficient group was lower than that of the control and folate-supplemented groups (55 versus 90 and 75%, respectively, P = 0.043). Kaplan-Meier analyses also demonstrated a similar trend in the rates of appearance of either adenoma or adenocarcinoma (P = 0.06). In contrast, folate supplementation did not significantly modulate mammary tumorigenesis compared with the control group. Although mammary tumors were significantly hypomethylated compared with non-neoplastic mammary tissues in each dietary group (P < 0.03), folate status did not significantly affect the extent of DNA methylation. The data suggest that dietary folate deficiency of a moderate degree suppresses, whereas folate supplementation at four times the basal dietary requirement does not significantly modulate, mammary tumorigenesis in this model. The role of folate in mammary tumorigenesis needs to be clarified for safe and effective prevention of breast cancer.
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Ontario, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Kotsopoulos
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Sohn
authors.forename: Rochelle
authors.initials: R
authors.lastname: Martin
authors.forename: Monica
authors.initials: M
authors.lastname: Choi
authors.forename: Richard
authors.initials: R
authors.lastname: Renlund
authors.forename: Colin
authors.initials: C
authors.lastname: McKerlie
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hwang
authors.forename: Alan
authors.initials: A
authors.lastname: Medline
authors.forename: Young-In J
authors.initials: YI
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000235:genetics; D004032:Diet; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood; D005494:Folic Acid Deficiency / Q000150:complications* / Q000378:metabolism; D015994:Incidence; D008099:Liver / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000477:Alkylating Agents; D004273:DNA, Neoplasm; D008770:Methylnitrosourea; D005492:Folic Acid