PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression

PTEN loss, one of the most frequent mutations in prostate cancer (PC), is presumed to drive disease progression through AKT activation. However, two transgenic PC models with Akt activation plus Rb loss exhibited different metastatic development: Pten/RbPE:-/- mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas RbPE:-/- mice deficient for the Src-scaffolding protein, Akap12, induced high-grade prostatic intraepithelial neoplasias and indolent lymph node dissemination, correlating with upregulated phosphotyrosyl PI3K-p85a. Using PC cells isogenic for PTEN, we show that PTEN-deficiency correlated with dependence on both p110ß and AKT2 for in vitro and in vivo parameters of metastatic growth or motility, and with downregulation of SMAD4, a known PC metastasis suppressor. In contrast, PTEN expression, which dampened these oncogenic behaviors, correlated with greater dependence on p110a plus AKT1. Our data suggest that metastatic PC aggressiveness is controlled by specific PI3K/AKT isoform combinations influenced by divergent Src activation or PTEN-loss pathways. Overall design: Four high-grade PIN lesions from Akap12/Rb-null mice (Pr_14273, Pr_14345, Pr_14354, Pr_14433). Two PC tumors from Pten/Rb-null mice (PT_T57, PT_173PT) are available in GSE90891 as samples GSM2417050 and GSM2417051, respectively.