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 GSK3ß 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.

Diversity of insulin and IGF signaling in breast cancer: Implications for therapy.

This review highlights the significance of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway in cancer and assesses its potential as a therapeutic target. Our emphasis is on breast cancer, but this pathway is central to the behavior of many cancers. An understanding of how IR/IGF-1R signaling contributes to the function of the normal mammary gland provides a foundation for understanding its aberrations in breast cancer. Specifically, dysregulation of the expression and function of ligands (insulin, IGF-1 and IGF-2), receptors and their downstream signaling effectors drive breast cancer initiation and progression, often in a subtype-dependent manner. Efforts to target this pathway for the treatment of cancer have been hindered by several factors including a lack of biomarkers to select patients that could respond to targeted therapy and adverse effects on normal metabolism. To this end, we discuss ongoing efforts aimed at overcoming such obstacles.