Each year 1.1 million new cases of breast cancer occur among women worldwide and ~50% of the patients succumb to metastatic disease. Although the biology of metastasis has been intensively studied, the cellular and biochemical mechanisms orchestrating its steps remain largely elusive. In this proposal, I will study the metabolic rewiring accompanying breast tumorigenesis and metastasis. Switching of metabolism can be controlled by oncogenic pathways, such as the PI3K/AKT pathway, which is frequently activated in breast cancer through PIK3CA mutations. The host lab has created unique in vivo breast cancer models induced by mutant PIK3CA. Their preliminary data suggest that transformation and metastasis in these models is accompanied by metabolic changes, which present a unique window for therapeutic targeting. In this proposal, I intend to explore the role and molecular details of selected metabolic regulators induced by PI3K mutants during tumor cell migration, invasion and metastasis in vitro and in vivo. To this end, I will combine state-of-the-art gene expression and bioinformatic analysis, metabolomics and multiphoton intravital imaging . Furthermore, I will employ RNAi screens to identify global key metabolic regulators that are essential for breast cancer adaptation to metastatic sites. This study should lead to the identification of new biomarkers and/or targets for metastatic breast cancer.