The natural history of human breast cancer is characterized by the progressive selection and outgrowth of cells that possess increasingly aggressive properties, such as loss of hormone dependence, resistance to chemotherapeutic agents, and the ability to invade tissues and metastasize. Moreover, by the time that breast cancers are diagnosed tumor cells may already have disseminated to distant sites where they can exist in a state of tumor dormancy. Consequently, breast cancers that appear cured may resurface as local or distant recurrences 10 or 20 years later. Collectively, the processes by which tumors become resistant to therapy, metastasize, establish tumor dormancy, and eventually recur are referred to as tumor progression. Importantly, these processes are responsible for nearly all breast cancer deaths. Nevertheless, while tumor progression constitutes a problem of unrivaled clinical importance, the mechanisms underlying it are largely unknown. As such, elucidating the molecular, cellular, and pathophysiological events that contribute to tumor progression is a critical priority in breast cancer research.

The biological and technical challenges to studying tumor progression and metastasis are considerable, likely explaining why this field has been termed "one of the last great frontiers of cancer biology." These challenges arise from the fact that metastasis affects multiple sites and organ systems throughout the body and must therefore be studied in whole animals rather than in cells or tissue culture. Adding to this complexity is the fact that the process by which cancers spread to distant sites consists of numerous steps. Each of these steps must be studied and understood in the context of the others, as well as in the context of the whole organism. Additional features of tumor progression, such as tumor dormancy, add even more complexity to the goals of improving breast cancer treatment and reducing or eliminating breast cancer mortality.

In this Center of Excellence, we propose to take on this challenge by applying a comprehensive battery of highly innovative, technically challenging noninvasive imaging methods to a series of state-of-the-art genetically engineered mouse models that faithfully recapitulate the key features of human breast cancer progression. By defining the mechanisms by which breast cancers progress, this Center of Excellence will significantly improve our understanding of the basis for the aggressive behavior of subsets of human breast cancers. In addition, determining how and where breast cancer cells become dormant should lead to improved methods for finding and eradicating those cells. This information is essential for understanding why breast cancer kills. We anticipate that our findings will lead to the development of more effective therapeutic approaches against highly aggressive forms of this disease by identifying the critical molecular targets and pathways by which breast cancers progress.

In addition, the clinical management of breast cancer patients would be helped significantly by the identification of noninvasive imaging approaches capable of detecting the early response of breast cancers to therapy and of predicting tumor response to therapy. This would enable more informed decisions to be made regarding therapies that are likely to work in a given patient, as well as permit the more rapid determination of therapies that do not work so that new ones can be initiated. Since many of the imaging instruments and methods that we will employ are already in clinical use, the combination of genetically engineered mouse models and innovative imaging approaches proposed in this Center should help to identify noninvasive imaging methods for predicting aggressive tumor behavior and for detecting the early signs of tumor response to therapy.