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 GSK3b activity and suppression of MYC phosphorylation on threonine 58, thus reducing proteasome-mediated degradation of MYC and sus-taining active pS62-MYC function. A stable T58A-Myc mutant rescues CSC function in Irs2-/- cells, support-ing the role of this MYC stabilization in IRS2-dependent CSC regulation. These findings establish a mecha-nistic connection between the IIS pathway and MYC and highlight a role for IRS2-dependent signaling in breast cancer progression.

Automated summary

This study reveals that the insulin/insulin-like growth factor signaling pathway supports self-renewal of breast cancer stem cells through the activation and stabilization of MYC. This process is mediated by IRS2-PI3K signaling, which enhances MYC expression and reduces MYC degradation.