Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes

PLoS One. 2012;7(5):e36402. doi: 10.1371/journal.pone.0036402. Epub 2012 May 3.


The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Survival / genetics
  • Class I Phosphatidylinositol 3-Kinases
  • Cluster Analysis
  • Enzyme Activation / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Profiling
  • Gene Silencing
  • Humans
  • Indazoles / pharmacology
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phenotype*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Interaction Domains and Motifs / genetics
  • RNA Interference
  • Signal Transduction* / drug effects
  • Sulfonamides / pharmacology


  • 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
  • Indazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Sulfonamides
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human