Abstract
Abstract Background: Widespread loss of genomic DNA methylation is an early and consistent epigenetic event in cancer development including breast carcinogenesis. Folate, an essential co-factor in the transfer of one-carbon units, has been shown to modulate both cancer risk and genomic DNA methylation. We recently observed that folic acid (FA) supplementation provided in utero and in early postnatal life significantly increased risk of mammary tumors in the offspring in the dimethylbenzanthracene (DMBA) rat model. To determine a potential underlying mechanism of FA-mediated mammary tumor development, we investigated the association between global DNA methylation, DNA methyltransferase (DNMT) activity, FA supplementation, and mammary tumor status in the offspring. Methods: Female Sprague-Dawley rats were placed on a control diet (2 mg FA/kg diet) or a supplemented (5 mg) diet for 3 weeks prior to breeding and throughout pregnancy and lactation. At weaning, female pups were randomized to the control or supplemented diet. At 7 weeks of age, all pups received a single intragastric dose (5 mg) of DMBA to induce mammary tumors. At 28 weeks of age, plasma, mammary gland and liver folate and plasma homocysteine concentrations were determined and mammary tumors were enumerated and histologically confirmed. Genomic DNA methylation and DNMT activity were determined in non-neoplastic mammary glands. Results: Plasma, liver, and mammary folate and homocysteine concentrations accurately reflected dietary FA levels at weaning and 28 weeks of age (p<0.05). A significant interaction was observed between genomic DNA methylation and mammary adenocarcinoma status in the offspring (p<0.001), indicating that among tumor-free offspring, genomic DNA methylation was significantly decreased by maternal FA supplementation. In addition, in offspring bearing at least one adenocarcinoma, genomic DNA methylation was significantly decreased regardless of dietary FA intervention. Postweaning FA supplementation independently decreased DNMT activity in the offspring (p=0.05). Conclusions: Our data suggest that decreased genomic DNA methylation and DNMT activity associated with maternal and postweaning FA supplementation might be a mechanism by which maternal and postweaning FA supplementation increased mammary tumorigenesis in the offspring. Given the drastic increase in FA intake among women of childbearing age in North America, future studies are need to determine whether or not FA supplementation increases the risk of breast cancer through epigenetic mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 942.
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