Breast cancer is the most frequently occurring cancer in women. Military women are at increased risk of breast cancer. The mortality and morbidity from breast cancer is due to its metastatic spread. The role of AMPK in tumorigenesis is controversial. Although AMPK inhibition was implicated in promoting tumorigenesis, we showed, several years ago, that AMPK activation is required for tumor cells survival during solid tumor formation. In recent years this assertion was independently corroborated by others in various types of cancer. In this grant application we propose that AMPK and its downstream effector the fatty acid translocase, CD36, are required for breast cancer metastasis. It is known that high ROS levels in disseminating cells is an impediment for metastasis and therefore the metabolic rewiring of key signaling pathways is critical to confer enhanced antioxidant metabolism to overcome this hurdle. Combating high ROS levels during metastatic colonization requires increased glucose uptake and utilization. We propose that the excess of ROS levels in disseminating breast cancer cells is a consequence of impaired glucose uptake and utilization. This impairment inhibits the oxidative pentose phosphate pathway (oxPPP) that generates NADPH to combat ROS. The limited glucose utilization during dissemination also leads to the activation of AMPK. By inhibiting fatty acid synthesis (FAS) and by elevating fatty acid oxidation (FAO), AMPK could maintain intracellular NADPH levels to combat ROS even when glucose utilization is impaired. In the first part of this grant application we will delineate the mechanism by which AMPK activation is required for breast cancer metastasis. In the second part of the grant application we will determine if the fatty acid translocase, CD36, is required for tumorigenesis and metastasis mediated by AMPK activation, and whether CD36 could be systemically targeted to inhibit breast cancer metastasis. We will use human breast cancer cell lines and PDOs and orthotopic transplantation as well as a mouse models for breast cancer metastasis in these studies. The proposed studies have a translational impact as they will determine whether drug therapy that activates AMPK directly or indirectly could have worse outcomes with respect to breast cancer metastasis, and whether targeting CD36 could inhibit breast cancer metastasis particularly in obese patients.