Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling

Nat Commun. 2015 Jan 27;6:6118. doi: 10.1038/ncomms7118.

Abstract

Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumours with OCCC-like histopathology, culminating in haemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting the tumour cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodelling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signalling. We propose that ARID1A protects against inflammation-driven tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / drug therapy
  • Adenocarcinoma, Clear Cell / genetics*
  • Adenocarcinoma, Clear Cell / pathology
  • Alleles
  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cytokines / metabolism*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation / drug effects
  • Female
  • Genes, Tumor Suppressor
  • Haploinsufficiency / drug effects
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Interleukin-6 / metabolism
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction / drug effects
  • Survival Analysis

Substances

  • Arid1a protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Interleukin-6
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pik3ca protein, mouse

Associated data

  • GEO/GSE57380