Dr Graham Burdge
Faculty of Medicine
Southampton General Hospital
Southampton, UK
Project title
Folic acid, epigenetic regulation of BRCA genes and DNA repair in healthy and cancer cells (2011/420)
Scientific abstract
BACKGROUND: The breast cancer associated genes BRCA1 and 2 are critical for repair of double stranded DNA damage in all cells. Silencing or decreased transcription due to hypermethylation of BRCA promoters is causally involved in sporadic breast and ovarian cancer. Interventions that alter the methylation of BRCA genes may, therefore, reduce the risk of cancers involving BRCA genes. Folate is a critical cofactor in 1-carbon metabolism linked to DNA methylation. Folate status has been shown to negatively associated with risk of some cancers including breast and ovarian. However, the effect of folic acid on other cancers is unclear. Our unpublished data show that folic acid supplementation of juvenile rats induced a tissue-specific persistent changes in the methylation of BRCA1 which were associated with altered mRNA and protein expression. Such tissue-specific effects may contribute to variations in the effect of dietary folate or folic acid intake on cancer risk. Also, normal and cancer cells from the same tissue respond differently to folic acid supplementation. Understanding the mechanisms that underlie the tissue-specific effects of folic acid on BRCA1 transcription is important in order to develop safe and effective recommendations for folic acid intake.The aim of this project is test the hypothesis that folic acid treatment induces, through altered epigenetic regulation, dose-dependent, cell-specific changes in BRCA1 and 2 transcription, and so modifies capacity for protection against DNA damage.
OBJECTIVES: We will use a range of human primary cells and cancer cell lines, obtained commercially, to determine the dose-dependency, tissue-specificity and stability of the effects of folic acid supplementation on the epigenetic regulation of BRCA1 and 2 transcription, protein expression, and DNA repair capacity in vitro.
METHODS: Cells will be treated in vitro for 3 days with a range of concentrations of folic acid which encompass the physiological range of serum folate. Cells will be harvested (n=10 cultures/treatment). Cells will be analysed for BRCA1 and 2 mRNA expression by quantitative RTPCR, protein expression by western blotting and DNA repair capacity following irradiation by pulse field gel electrophoresis. The methylation of the BRCA1 and 2 promoters will be measured by pyrosequencing. The function of CpG dinucleotides which are altered by folic acid treatment will be determined by cloning of native and mutated BRCA 1 and 2 promoters into expression vectors containing a Luciferase reported gene.
IMPACT: The findings of this project will provide novel insights into how folic acid supplementation may alter risk of cancer and the molecular basis of differences between tissues in the effect of folic acid on BRCA 1 and 2 activity. The findings of this study will contribute to understanding how nutrients modify cancer risk and so inform dietary recommendations folic acid and folate intake to the general population, and to those at risk of cancers involving BRCA genes. This information will also inform the current policy debate on folic acid fortification of foods. Understanding the role of epigenetic processes in the regulation of BRCA1 and 2 by the diet may provide novel targets of nutritional interventions to reduce cancer risk.
Plain language abstract
BACKGROUND: The genes BRCA 1 and 2 are important for repairing damaged DNA in all cells and so prevent the formation of cancers. Impaired function of these genes is important in cancers of the breast and ovary. However, most of these cancers do not involve mutations in BRCA genes. Instead, the processes which control how these genes work are altered in a way that reduces their ability to repair damaged DNA. The vitamin folic acid is involved in controlling the function of BRCA genes. Our findings show that more folic acid may increase the activity of the BRCA genes in some cells, but decrease it on others. In order to make safe dietary recommendations for consumption of folic acid, including dietary changes to prevent or help treat cancers, we need to understand why different tissues respond differently to folic acid.
AIMS and GOALS: We will test in the laboratory how different types of cells, normal and cancer, respond to folic acid treatment. We will then investigate how this affects the control of the BRCA genes and their ability to repair damaged DNA.
POTENTIAL IMPACT: We hope this project will tell us how folic acid alters risk of different cancers. In so doing we aim to clarify some of the uncertainty about the effects of folic acid on cancers shown in previous studies. This will help nutritionists devise dietary recommendations for folic acid intake to the general population and to those at risk of cancers involving BRCA genes. Understanding how folic acid alters the control of the BRCA1 and 2 genes may lead to treatments that use nutrients to reduce cancer risk. The findings of this study will also contribute to the wider understanding about how nutrients modify cancer risk.
Qualifications
Institution and location |
Degree |
Year |
Scientific field |
The University College of Wales |
BSc (Hons.) |
1985 |
Cell and Immunobiology |
University of Southampton |
PhD |
1990 |
Medical Oncology |
Previous employment
2009 - present |
Reader in Human Nutrition, Faculty of Medicine, University of Southampton |
2007 - 2009 |
Lecturer in Human Nutrition, University of Southampton. |
2006 - 2007 |
British Heart Foundation Research Fellow, University of Southampton |
2003 - 2005 |
Senior Research Fellow, University of Southampton |
1998 - 2003 |
Research Fellow, School of Medicine, University of Southampton |
1997 - 1998 |
Scientific Officer, Veterinary Laboratories Agency, Surrey |
1995 - 1997 |
Senior Research Fellow, University of Southampton |
1989 - 1995 |
Postdoctoral Research Fellow, University of Southampton |
1989 - 1989 |
Basic Grade Microbiologist, PHLS CAMR, Wiltshire. |
Research interests
Dr Burdge research is focused on the interaction between nutrition and the epigenome in determining individual variation in metabolic capacity and in differential risk on non-communicable diseases.
