FOXOs Maintaining the Equilibrium for Better or for Worse

A paradigm shift is emerging within the FOXO field and accumulating evidence indicates that we need to reappreciate the role of FOXOs, at least in cancer development. Here, we discuss the possibility that FOXOs are both tumor suppressors as well as promoters of tumor progression. This is mostly dependent on the biological context. Critical to this dichotomous role is the notion that FOXOs are central in preserving cellular homeostasis in redox control, genomic stability, and protein turnover. From this perspective, a paradoxical role in both suppressing and enhancing tumor progression can be reconciled. As many small molecules targeting the PI3K pathway are developed by big pharmaceutical companies and/or are in clinical trial, we will discuss what the consequences may be for the context-dependent role of FOXOs in tumor development in treatment options based on active PI3K signaling in tumors.