During the last 20 years, we have been characterizing mice with different Akt isoforms deficiencies for survival, lifespan, and susceptibility to cancer at the cellular and organismal levels. The current renewal application is focused on the systemic effect of Akt isoforms deletion in adult mice. First, the systemic deletion of Akt1 and Akt2 as well as moderate to high doses of pan-Akt inhibitor in adult mice induces intestinal damage, loss of body weight, and eventually mortality. Thus, in the first part of this grant application we will delineate the mechanism of the intestinal damage and will employ approaches to alleviate it. Second, we found a marked discrepancy between the systemic effect and cell autonomous effect of Akt1 or Akt2 deletion on tumor initiation, progression, and metastasis. These results underscore the importance of determining the systemic effect of gene targeting for cancer therapy. We will delineate the mechanisms by which the systemic deletions of Akt1 or Akt2 in adult mice exert their effects on tumor progression and metastasis in mouse models of breast cancer.