Project 464539

Breast cancer metastasis to distant organs in general and to the skeleton in particular are a major cause of cancer associated morbidity and mortality. These patients are generally in advanced stages when no effective therapies are available. Cancer initiation and progression is regulated by genes which activate key intracellular signaling pathways. Our genes are regulated by a set of chemical marks on DNA called DNA methylation. Interestingly, we identified a protein methyl-CpG-binding domain protein 2 (Mbd2) that is responsible for this loss of DNA methylation. Inhibition of MBD2 expression in cell culture and in animal models of breast cancer results in blocking the expression of cancer promoting genes. In this study different mouse models of breast cancer metastasis as well as human metastasizing breast cancer cells will be implanted in mice to test the hypothesis that blocking MBD depletion by genetic and chemical inhibitors blocks breast cancer growth and metastasis. The study will examine in depth the underlying mechanism of action of these agents, identify and validate the role of these these genes in breast cancer. Highly selective inhibitors of MBD2 and MBD2 mediated pathways will be examined for their efficacy in mouse models of breast cancer. Results from these studies will lead to the evaluation of these agents alone and in combination setting in breast cancer patients.