Data from PP2A Inactivation Mediated by <i>PPP2R4</i> Haploinsufficiency Promotes Cancer Development

<div>Abstract<p>Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here, we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of <i>PPP2R4</i>, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in <i>PPP2R4</i>. Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles. In <i>Ppp2r4</i> gene-trapped (gt) mice showing residual PTPA expression, total PP2A activity and methylation were reduced, selectively affecting specific PP2A holoenzymes. Both PTPA<sup>gt/gt</sup> and PTPA<sup>+/gt</sup> mice showed higher rates of spontaneous tumors, mainly hematologic malignancies and hepatocellular adenomas and carcinomas. These tumors exhibited increased c-Myc phosphorylation and increased Wnt or Hedgehog signaling. We observed a significant reduction in lifespan in PTPA<sup>+/gt</sup> mice compared with wild-type mice. In addition, chemical-induced skin carcinogenesis was accelerated in PTPA<sup>+/gt</sup> compared with wild-type mice. Our results provide evidence for <i>PPP2R4</i> as a haploinsufficient tumor suppressor gene, defining a high-penetrance genetic mechanism for PP2A inhibition in human cancer. <i>Cancer Res; 77(24); 6825–37. ©2017 AACR</i>.</p></div>