Grant: Operating Grant

Metastasis of cancer cells to other organs is responsible for a large fraction of the morbidity and mortality from breast cancer. There are no effective therapies that could block breast cancer metastasis. A large number of genes play a role in breast cancer metastasis; we therefore reasoned that inhibiting metastasis would be possible only if the principal process that coordinates the activation of a significant fraction of these genes is reversed or inhibited. Our genes are regulated by a set of chemical marks on DNA called DNA methylation. DNA methylation silences genes. Our labs have discovered in previous studies that the process that turns on metastatic genes in cancer involves the removal of DNA methylation. Interestingly, we identified a protein that is responsible for this loss of DNA methylation, MBD2. We also discovered that if we used specific drugs that blocked the process of removal of DNA methylation, cancer metastasis was inhibited as well. Interestingly, the process of metastasis could be blocked with (S-adenosylmethionine) SAMe a natural compound. This compound interferes with DNA demethylation and MBD2 activity. These studies were mostly done in tissue culture. However, to know whether SAM could serve as a therapy in human breast cancer it has to be tested first in living animals. In this study we are going to use different mouse models of breast cancer metastasis as well as human metastasizing breast cancer cells explanted in mice to test the hypothesis that depletion of MBD2, or treatment with SAMe reverse and prevent breast cancer metastasis. The study will look as well at the mechanism of action of these agents. Since SAMe is an approved nontoxic nutritional supplement this study could be translated into new therapeutics and preventatives of breast cancer metastasis.