Cancer Stem Cell‐Like Phenotype and Survival Are Coordinately Regulated by A kt/ F oxO/ B im Pathway

Many solid tumors contain a subpopulation of cells with stem characteristics and these are known as cancer stem cells (CSCs) or tumor‐initiating cells (TICs). These cells drive tumor growth and appear to be regulated by molecular pathway different from other cells in the tumor bulk. Here, we set out to determine whether elements of the PI3K‐AKT pathway are necessary to maintain the CSC‐like phenotype in breast tumor cells and for these cells to survive, bearing in mind that the identification of such elements is likely to be relevant to define future therapeutic targets. Our results demonstrate a close relationship between the maintenance of the CSC‐like phenotype and the survival of these TICs. Inhibiting PI3K activity, or eliminating AKT activity, mostly that of the AKT1 isoform, produces a clear drop in TICs survival, and a reduction in the generation and growth of CD44 High /CD24 Low mammospheres. Surprisingly, the apoptosis of these TICs that is triggered by AKT1 deficiency is also associated with a loss of the stem cell/mesenchymal phenotype and a recovery of epithelial‐like markers. Finally, we define downstream effectors that are responsible for controlling the CSC‐phenotype, such as FoxO‐Bim, and the death of these cells in the absence of AKT1. In summary, these data closely link the maintenance of the stem cell‐like phenotype and the survival of these cells to the AKT‐FoxO‐Bim pathway. S tem C ells 2015;33:646–660