Impact of methyl-group donor intakes on breast cancer risk: integrating findings from large-scale epidemiological studies and in vitro models

DNA methylation is the most extensively studied mechanism of epigenetic gene regulation, a
biological mechanism that will switch genes on and off. The universal methyl-group donor for DNA
methylation is S-adenosylmethionine (SAM), which is provided by one-carbon metabolism. Methyl donors like methionine, folate, betaine and choline are micronutrients which are essential to the
decent functioning of one-carbon metabolism. Aberrations in this pathway by deficiency or excess
in any of these micronutrients, could affect the DNA methylation process. Improper alterations in
DNA methylation patterns can affect normal patterns of gene expression or alter genome stability
and thereby lead to an increased risk of cancer. Therefore, the objective of the present project is
to examine the hypothesis that dietary intake of methyl-group donors involved in one-carbon
metabolism may influence breast cancer risk through alterations in DNA methylation patterns. To
investigate this hypothesis, the existing resources of the European Prospective Investigation into
Cancer and nutrition (EPIC) study will be used to address the major gaps in the understanding of
the role of methyl donor nutrients, DNA methylation and breast cancer development by applying a
nutri-epigenetic approach. Simultaneously, an in vitro model will be developed to examine the
effects of methyl- group donor exposure on epigenetic changes in breast cell lines. This can
contribute to the understanding of the mechanisms of action.