GPCR Signaling Mediates Tumor Metastasis via PI3Kβ

Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3K alpha, a role for PI3K beta has begun to emerge. The PI3K beta isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein-coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3K beta binding to Gb gamma (p110(526KK-DD)). Expression of this mutant in p110 beta-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3K beta in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease. (C) 2016 AACR.