The effect of the level and timing of folic acid supplementation during the lifecourse on the epigenetic regulation of cancer determining genes and implications for genome stability and tissue differentiation

  • Topic: Breast Cancer
  • Institution: University of Southampton
  • Country: United Kingdom
  • Status: Ongoing

Scientific abstract

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Background

The relationship between folic acid and cancer is uncertain as although most studies have shown that in adults moderate folic acid intake reduces breast cancer risk, there is also evidence that folic acid at high levels can increase susceptibility to cancer. However, to date few studies have explored the relationship between early life exposure to folic acid and later risk of breast cancer, despite evidence that environmental exposures in early life are important determinants of future disease risk. Preliminary work in our laboratory has shown that folic acid intake during specific periods in development results in altered DNA methylation and long term changes in the expression of BRCA1 and Oct4, genes involved in breast cancer risk. These findings suggest that susceptibility to cancer in adults may originate at least partly from epigenetic changes induced decades before the appearance of clinical disease by variations in micronutrient intake during key developmental periods.

Hypothesis & Objectives

This proposal addresses the general hypothesis that folic acid intake during specific periods of the life-course leads to persistent dose and tissue-dependent epigenetic changes in genes involved in determining cancer risk.

  1. To determine whether the timing and level of folic acid supplementation during the life course induces long-term changes in the expression of BRCA 1 and Oct-4.
  2. To determine whether persistent alterations in gene expression induced by folic acid supplementation involve changes in DNA methylation.
  3. To determine whether the altered expression of BRCA1 and Oct-4 induced by folic acid supplementation leads to alterations in DNA repair, cell differentiation and tissue morphology.

Settings & Methods

  1.  To determine whether folic acid supplementation across a range of concentrations during juvenile or adult life induces persistent changes in the mRNA and protein expression of BRCA1 and Oct4.
  2.  To determine whether the alterations in gene expression induced by folic acid supplementation involve changes in DNA methylation.
  3.  To determine whether the altered expression of BRCA1 and Oct-4 leads to an altered sensitivity to DNA damage and mammary gland morphology.

Potential Impact 

This project will provide novel insights into the mechanism by which folic acid supplementation affects cancer risk and how the level and timing of folic acid supplementation affects this response. Thus these findings will guide current discussions on folic acid fortification and aid the development of safe and effective recommendations for folic acid intake. In addition insights into the regulation of BRCA1 and OCT-4 by nutritional factors may aid the development of novel intervention strategies to reduce breast cancer risk.

Plain language abstract

Background

Folic acid intake has been shown in most studies to reduce breast cancer risk, however there are some studies which show that high levels of folic acid may increase cancer risk. However to date few studies have examined the impact of high folic acid intake during early life despite growing evidence that early life is a critical period when a number of environmental factors including nutrition can have life long effects on our growth, physiology and subsequent disease risk. Our studies have shown that folic acid supplementation in early life can alter the activity of key cancer determining genes, BRCA1 which regulates DNA repair, and Oct-4 which controls cell growth. Given that folic acid intake has risen rapidly over the past ten years it is vital that the impact of high folic acid intake during different period of the life course is assessed and the effect on these key cancer determining genes determined.

Aims & Goals

We will examine the effect of folic acid dose during different periods of the lifecourse on the activity of BRCA1 and OCT-4, the ability to repair DNA and the effect on mammary gland structure and function.

How it will be done

1. To determine whether folic acid supplementation across a range of concentrations during juvenile or adult life induces persistent changes in the mRNA and protein expression of BRCA1 and Oct4.
2. To determine whether the alterations in gene expression induced by folic acid supplementation involve changes in DNA methylation.
3. To determine whether the altered expression of BRCA1 and Oct-4 leads to an altered sensitivity to DNA damage and mammary gland morphology.

Potential impact

This project will assess the effect of the level and timing of folic acid intake on cancer susceptibility, clarifying the relationship between folic acid and cancer risk. These studies will also guide discussions about dietary recommendations for folic acid intake. This project will also provide valuable insights into how the key cancer determining genes BRCA1 and Oct-4 are controlled by nutritional factors which may lead to the development of new strategies to modify their activity and thereby reduce cancer risk.