The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC.

Despite the strong association of the insulin/insulin-like growth factor (IGF) signaling (IIS) pathway with tumor initiation, recurrence, and metastasis, the mechanism by which this pathway regulates cancer progression is not well understood. Here, we report that IIS supports breast cancer stem cell (CSC) self-renewal in an IRS2-phosphatidylinositol 3-kinase (PI3K)-dependent manner that involves the activation and stabilization of MYC. IRS2-PI3K signaling enhances MYC expression through the inhibition of GSK3β activity and suppression of MYC phosphorylation on threonine 58, thus reducing proteasome-mediated degradation of MYC and sustaining active pS62-MYC function. A stable T58A-Myc mutant rescues CSC function in Irs2 ^−/− cells, supporting the role of this MYC stabilization in IRS2-dependent CSC regulation. These findings establish a mechanistic connection between the IIS pathway and MYC and highlight a role for IRS2-dependent signaling in breast cancer progression. [Display omitted] • Insulin/IGF signaling (IIS) supports breast cancer stem cell (CSC) self-renewal • IIS regulates stemness in an IRS2- and PI3K-dependent manner • IRS2/PI3K signaling activates and stabilizes MYC to enhance CSC function Lee et al. show that the insulin/IGF signaling pathway regulates breast cancer stem cell (CSC) function in an IRS2- and PI3K-dependent manner. This regulation involves the activation and stabilization of MYC, as shown by the ability of a stable T58A-MYC mutant to restore CSC function in IRS2 ^−/− cells. [ABSTRACT FROM AUTHOR]