The Mechanism of DNA Demethylation in Breast Tumorigenesis

PUBLIC ABSTRACT

DNA methylation is generally associated with silenced expression of the methylated sequence. DNA methylation protects against genomic instability ¿ mutations or rearrangements in the DNA of a cell. In sixty percent of breast cancers, there is a loss of DNA methylation which results in expression of tumor promoting genes and increased genomic instability. In addition, there are links between DNA demethylation and the development of tumor resistance to chemotherapeutic drugs.

Scientists are unaware of how DNA demethylation occurs. Despite extensive searches, no enzymes with the ability to remove a methyl group have been identified. Mutations or changes in the expression levels of the methyltransferase enzymes that add the methyl groups to DNA have been ruled out. I will determine how DNA demethylation happens and identify the genes involved.

The genes responsible for the demethylation phenotype are ideal breast cancer therapeutic drug targets as a majority of breast tumors show demethylation. Restoration of methylation will silence oncogenes and should decrease genomic instability, which is essential for the development of resistance to treatment. The identification of these genes will facilitate the development of novel therapy avenues.

The main indicator of a patient¿s prognosis following a diagnosis of breast cancer is the stage of the disease. The ten-year survival rate is 80% for T1N0M0 breast adenocarcinoma but falls to 50% when one lymph node is involved. However, metastatic breast cancer is not curable; mean survival is 18-24 months following diagnosis. The key to decreasing mortality from breast cancer is early detection, which requires the identification of novel biomarkers for diagnostic tests. My research involves the characterization of the frequency of hypomethylation and expression of a normally silenced human tandem repeat sequence on chromosome 8 as a potential breast cancer biomarker. Moreover, I will characterize a number of novel breast cancer hypomethylated regions in my panel of cell lines, which may lead to the identification of other biomarkers. As tumor genomes have a net loss of DNA methylation, a much greater portion of the genome is affected by hypomethylation than hypermethylation. Assays that examine repeat sequences are hundreds to thousands of times more sensitive than assays of single copy sequences.

As an MD/PhD student, I will one day become a breast cancer physician scientist. My basic research uncovering the mechanism of DNA demethylation in tumors and identifying novel breast cancer biomarkers will give me the background needed to begin to transition these principles into the clinic. My future clinical research will involve developing and implementing novel diagnostics based on the innovative methylation-specific assays developed in the Bestor lab. In addition, I will run clinical trials on drugs developed subsequent to my basic research on the genes involved in breast cancer demethylation.