Novel hypermethylated tumor suppressor genes as indicators of decitabine sensitivity in breast cancer

Clinically relevant breast cancer research will improve treatments for patients. The focus of this project is to develop a new breast cancer treatment strategy while simultaneously identifying genes that are vital to breast tumor growth. First, it is important to note that not all breast cancer patients will respond well to the same treatment, and that their response is often dependent on what is driving growth of their unique tumor. Many tumors grow based on dysfunctional DNA methylation. Methylation can effectively "turn off" genes (silence genes) by adding a methyl group directly to the DNA sequence of that gene. When a normal breast cell acquires methylation that silences anti-cancer genes; the loss of these genes can cause cancer. There is an existing therapy called decitabine which is able to remove methyl groups on DNA; this drug is currently used to treat some blood cancers and is in clinical trials for solid tumors (including breast cancer). Theoretically, removing methyl groups via decitabine should turn anti-cancer genes back on and should slow breast tumor growth. However, as with any other therapy not all patients will benefit equally from this treatment. To find the patients who will benefit the most from decitabine therapy, we first must identify the key methylated anti-cancer genes. My approach to identify key anti-cancer genes is unique and clinically relevant as I will identify only those methylated genes which are clearly playing a role in breast cancer progression and are "druggable" by decitabine. Mice that have been given human breast cancer tumors will be treated with decitabine and then we will determine how well methylation of the breast cancer tumors predicts the tumors' response to decitabine. We will examine all the genes in the genome to determine how loss of expression / resurrection of expression (via decitabine) influenced tumor growth. This study will lead to a pre-clinical model identifying decitabine-responsive patients.