Breast cancer is a leading cause of cancer death in women worldwide. Most breast cancer deaths are due to metastatic progression, that is, spread of cancer cells to distant sites in the body. Thus, preventing the development of and successfully treating metastatic disease are among the most important aims in breast cancer research. The central tenet underlying our work is that master regulators of breast cancer are fundamentally important for the metastatic process and that systematic understanding of these changes will be of tremendous clinical diagnostic value and help lay the foundation for effective treatments to eradicate breast cancer. Our rationale is that understanding the ultimate drivers of metastasis is a crucial step in achieving the goal of a cure for metastatic disease. Through a systematic approach employing global, large-scale analysis of primary tumors and metastases and functional models using human breast cancer cells with varying metastatic potential, we will work to elucidate the mechanisms underlying our candidate master regulators of breast cancer metastasis. We will then develop compounds to target these candidates using novel drugs. If successful, our work would have broad applicability to breast cancer patients (with both hormone positive and negative tumors), particularly for patients with metastatic and node-positive disease. Elucidating how our candidate master regulators of metastasis cause metastasis and developing methods to inhibit them may potentially transform clinical management of breast cancer and open doors for future mechanistic studies.