Stabilization of IQGAP1 by the mTORC2 component PRR5 mediates mitogenic LINC01133-to-ERK signaling in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) lack targeted therapeutics that can inhibit their growth and progression. The long intergenic noncoding RNA LINC01133 promotes TNBC pathogenesis by increasing the abundance of proline-rich protein 5 (PRR5), an mTORC2 component that activates the kinase AKT in a PI3K-independent, mTORC2-dependent manner. Here, however, we found that TNBC cell proliferation was incompletely sensitive to AKT inhibitors alone because PRR5 also stimulated the mitogen-activated protein kinase (MAPK) cascade in an mTORC2-dependent manner. PRR5 associated with and prevented the ubiquitin-dependent proteasomal degradation of IQGAP1, an adaptor protein that promotes activation of the MAP kinase ERK. ERK signaling was essential for LINC01133-mediated TNBC proliferation in two- and three-dimensional cultures, and ERK inhibitors synergized with AKT blockade to suppress LINC01133-induced TNBC cell growth. Furthermore, PRR5 abundance was particularly enriched and correlated with that of phosphorylated ERK in samples from patients with TNBC. Our results highlight cross-talk between mTORC2 and ERK signaling downstream of LINC01133 and PRR5 that may be therapeutically targeted to treat TNBC.