Proposed is a continuation of a productive, integrated, innovative Program Project in animal and laboratory models of breast cancer with actual and prospective clinical translatability. The goal is to address fundamental biological questions to advance our knowledge of metastasis and aberrant growth regulation and thereby improve all aspects of breast cancer prognostication, prediction of therapeutic benefit, and treatment. It is comprised of four projects, each led by a leader in the field, an Administrative Core to provide oversight and management, and a highly innovative RNAi Core to provide critical reagents as well as genetically engineered mouse models. Avoidance of duplication of effort, intellectual and material synergy, and orientation toward real clinical needs are hallmarks of this effort. The Projects and their Principal Investigators are: (1) TGF-beta, PI3K and HER2 pathways in breast cancer metastasis (Joan Massague, Ph.D.), (2) Role and regulation of Id1 during breast cancer metastasis initiation (Robert Benezra, Ph.D.), (3) Development of mechanism-based strategies for the treatment of advanced breast cancer with PI3K pathway inhibitors (Neal Rosen, Ph.D. and Sarat Chandarlapaty, M.D.)' and (4) RND1 - Mediated breast cancer suppression (Filippo G. Giancotti, M.D., Ph.D.). Administrative Core A is to be led by Larry Norton, M.D., who is also the Principal investigator of the Program. The Core B in RNAi Tools for Breast Cancer Research is to be led by Scott Lowe, Ph.D.