This is a resubmission application for a K22 Career development award for Dr. David R. Soto Pantoja, an NCI-Cancer Training Award Fellow at, National Institutes of Health. Dr. Pantoja has extensive expertise in the areas of molecular biology and cancer biology. He has been successful in obtaining competitive support for his research through a Department of Defense predoctoral training award and as a postdoctoral fellow obtaining a NCI Directors Career Development Innovation Award. He has assembled a multidisciplinary committee and will participate in course work to complement his expertise in cancer biology to ensure the successful transition into an independent career. This grant will be essential for the completion of Dr. Pantoja's career goals. The objectives of this proposal are to find novel mechanisms to reduce tumor growth, overcome development of resistance to chemotherapy and reduce metastasis of breast cancer, which is responsible for over 40,000 deaths every year in the United States. Published evidence shows that blockade of CD47 enhances local radiation growth delay of tumors while protecting normal tissue. Dr. Pantoja's key publications show of that the mechanism of radioprotection with CD47 blockade is through activation of protective autophagy. This application proposes that this mechanism is activated to sensitize cancer cells to therapy by the selective activation of mitophagy increasing mitochondrial turnover. Cancer cells develop resistance to chemotherapy in part to accumulation of mitochondria leading to increase in reactive oxygen species that stimulate pro-survival pathways. The current mechanism to overcome this issue is poorly understood. Therefore it is proposed in this application that blockade of CD47 sensitizes breast cancer cells by regulating bioenergetics mainly by reducing the active glucose metabolism and through increased activation of mitophagy. This proposal is strengthened by the complementary and rich tool set used to investigate the hypothesis, the vast resources available within the National Cancer Institute and collaborators at the University of Pittsburgh and Georgetown University and captures the pioneering work of Dr. Pantoja's advisors in the areas of breast cancer resistance, cell bioenergetics, autophagy and the CD47 signaling axis. The combination of these fields and the completion of these studies will validate novel therapeutic targets for treating invasive breast cancer as well as other major cancers.