Sirt5 expression ensures the survival of breast cancer cells and restores their viability upon the knock-down of ATF4. Together, these results highlight a pro-survival mTORC2-dependent signaling pathway that culminates in the sustained expression of ATF4 and the upregulation of its transcriptional target Sirt5 to promote adaptive compensation to metabolic and oxidative challenges. Here, ATF4 is linked to breast cancer.