Although it is established that the Ets family of transcription factors control specific genes that contribute to normal and aberrant processes, identification of their roles in tumor metastasis remains an unresolved area requiring further investigation. Ets factors can be positive or negative regulators, and they can be intrinsic to the malignant cells or can affect stromal cells that indirectly influence cell movement. The members of this Program Project Grant will use in vitro and in vivo approaches to elucidate the upstream and downstream pathways that mediate Ets function, both in normal development and in cancer. The Program consists of three interactive Projects supported by three cores. Project 1 will test the hypothesis that the Ets factor PDEF controls multiple aspects of the multi-step metastatic process and therefore, loss of PDEF expression is a key event in the development of invasive breast cancer. Project 2 will examine a novel pathway in tumor cells that results in over-accumulation of a metastasis-inducing signaling receptor, FGF receptor;and analyze how Ets1 mediates this aberrant signaling event in promoting cell motility. Project 3 will further assess the mechanisms whereby Fli1 and Ets1 function as critical regulators of stromal homeostasis in healthy tissues, as well as their contribution to formation of reactive stroma in cancer. Specifically, Project 3 will test the hypothesis that Ets factors are integrators of the TGF-b/CTGF and Ras-MAPK signaling pathways in regulation of ECM remodeling. This in turn affects cell migration, cell survival and recruitment of perivascular cells to the newly formed vessels. Thus, the Program Project proposes experiments to elucidate the molecular pathways that underlie the roles of Ets factors in cell migration, invasion and metastasis and angiogenesis. The long-term goal of this Program is to gain new insights that will provide novel approaches for improved diagnosis and treatment of cancer.