The long-term goal of this research proposal is to elucidate mechanisms of breast cancer metastasis to bone. Approximately, 60-70 percent of breast cancer patients who have died or are dying of breast cancer have bone metastases. Osteonectin (OSN, SPARC, BM-40) is a bone factor that has been found to be a chemo-attractant for breast and prostrate cancer cells. In addition, increased OSN expression has been found in breast cancer, however a connection between increased OSN expression in breast cancer cells and bone metastasis has not been proven. Surprisingly, a cell surface receptor has yet to be identified. This proposal will test the central hypothesis that increased expression of OSN in breast cancer cells increases tumor growth and metastasis to bone, and binding of OSN to its cell surface receptor is important for this process. Specific aim 1 will determine if altered expression of OSN in breast cancer cells will affect tumor cell growth, invasion and protease activity in vitro and specific aim 2 will examine if this altered expression of OSN affects tumor cell growth in the mammary fat pad, in bone and in metastasis to bone in vivo. Specific aim 3 will establish if OSN binds to the cell surface and characterize the cell surface binding protein. A variety of approaches will be utilized to elucidate the role OSN in breast cancer bone metastasis and to identify OSN surface binding proteins. Identification of the OSN binding protein and determining the role of endogenous production of OSN by breast cancer cells may lead to better diagnostic and/or therapeutic approaches for breast cancer.