The major focus of our laboratory is to investigate the cell and molecular biology of cancer, with a focus on the PI 3-Kinase and AKT signaling pathway in cancer. We have investigated the regulation and function of the Akt/PKB and SGK protein kinases, major effectors of PI 3-K, one of the most frequently deregulated pathways in tumors. We discovered that Akt1 is breast cancer cell motility and invasion suppressor, a surprising finding considering that this pathway is implicated in tumor progression. The significance of these findings is that small molecule inhibitors of Akt, currently in clinical trials, may actually enhance tumor invasion and metastasis. We have also investigated the regulation of Akt and SGK isoforms by upstream signaling pathways, and most recently have focused on identifying novel substrates of Akt isoforms that mediate the responses to invasive migration in breast cancer progression. We have identified the first isoform-specific Akt1 substrate, the cytoskeletal regulatory protein palladin, that modulates invasive migration in breast cancer cells. We have also identified new mechanisms of oncogenic Akt and PI 3-K signaling through non-Akt-dependent signaling, such as SGK3, and mechanisms of PI3K bypass in the context of resistance to inhibitors used in the clinic. We also have provided insight into how oncogene addiction through PI3K and AKT induces reprogramming of metabolic pathways in cancer cells thereby providing metabolic vulnerabilities that can be targeted therapeutically. We have extended this line of investigation into exploring metabolic vulnerabilities that are exposed in cancers treated with standard of cancer cytotoxic chemotherapy, and revealed that glutathione biosynthesis and de novo pyrimidine synthesis represent vulnerabilities that can be targeted in combination with chemotherapeutic drugs. We have used chemical biology approaches to discover new drugs that inhibit AKT in human cancer with the goal of initiating new clinical trials. Finally, I have a major commitment to the mentoring and training of students and junior scientists, and I am deeply committed to graduate education through the BBS program.