The growth and metastatic spread of solid tumors is controlled by signals emanating from tumor cells as well as by immune cells and fibroblasts in the surrounding stroma, components of the extracellular matrix, and soluble growth factors and cytokines. While this complexity creates challenges for therapeutic intervention, it also provides unique opportunities by making available a number of distinct cellular and molecular targets that can be exploited to control tumor growth and progression. The focus of this proposal is on Focal Adhesion Kinase (FAK), a protein tyrosine kinase whose expression is significantly increased in many late-stage cancers, including breast cancer. We hypothesize that FAK expression in two components of the tumor microenvironment, the tumor cells and tumor-associated macrophages (TAMs), plays a critical role in promoting breast tumor progression and metastasis. We will use mouse models of breast cancer to gain an understanding of how FAK expression in breast carcinoma cells and/or the ancillary tumor-associated macrophages controls primary breast tumor growth and metastatic spread. By combining genetic manipulation of these mice with FAK inhibitors currently in Phase I clinical trials, we propose to 1) determine how the loss of FAK expression in macrophages alters or ablates macrophage functions that drive breast tumor growth/progression and metastasis (Aim 1);2) assess how the dual modulation of FAK expression in breast tumor cells and in tumor-associated macrophages alters breast tumor growth and metastasis (Aim 2A);and 3) assess how systemic inhibition of FAK expression alters breast tumor growth and metastasis (Aim 2B). Successful completion of this study will provide new insights into features of the tumor that can predict a clinical response to the FAK-targeted drugs currently in clinical trials and the optimal timing for these treatments. More globally, we will learn about mechanisms through which tumor cells and other cells within the tumor microenvironment communicate to promote breast tumor growth and metastasis. We anticipate that this work will help to move the paradigm for breast cancer treatment away from the tumor cells per se and toward the full complement of factors that contribute to tumor growth and metastasis. PUBLIC HEALTH RELEVANCE: By focusing on the role of FAK in both macrophages and tumor cells, this work will uncover novel features of macrophage - tumor cell synergy that contribute to breast tumor behaviors. In addition to providing critical information about how FAK inhibitors should be used to treat breast cancer patients, this work will potentially identify new strategies for targeting distinct cellular compartments within the tumor that can be exploited therapeutically to control tumor growth and progression. It is anticipated that, through the knowledge gained from these studies, there will be a significant reduction in mortality from breast cancer.