Breast cancer is a manifestation of abnormal genetic as well as epigenetic changes. Global hypomethylation, accompanied by promoter hypermethylation, is a common feature of breast tumor cells. Global hypomethylation is thought to induce chromosomal instability, reactivate transposons, promote loss of imprinting, and activate proto-oncogenes. Promoter hypermethylation, on the other hand, appears to be associated with inactivation of genes in virtually all pathways protective of carcinogenesis (e.g. DNA repair, cell cycle control, inflammatory/stress response, detoxification, apoptosis, etc.) including those of breast cancer.
One-carbon metabolism facilitates the cross-talk between genetic and epigenetic processes by playing critical roles in both DNA methylation and DNA synthesis. It provides essential cofactors in the production of primary methyl donors for methylation of DNA, RNA and protein, as well as of dUMP to dTMP in DNA synthesis. A low methyl supply induces DNA global hypomethylation as well as deficient methylation of dUMP to dTMP leading to uracil misincorporation. These processes may result in aberrant DNA repair leading to DNA strand breaks, enhanced mutagenesis and apoptosis. It is important to note that methylation patterns are subject to clonal transmission, and as a result disturbances in one-carbon metabolism can have long-term consequences even after one-carbon metabolism has returned to normal.
This talk will focus on our systematic investigation of the role of one-carbon metabolism in breast cancer etiology and survival. Using a population-based case-control study, Long Island Breast Cancer Study Project, we have examined the inter-relationships among dietary methyl intake, functional polymorphisms related to one-carbon metabolism, and methylation status in tumors. We hope to better elucidate the role of epigenetics in breast cancer development.
Acknowledgement: This work was supported by grants NIH CA109753, DOD BC031746, DOD W81XWH-06-1-0298.