Inhibiting Wnt/beta-catenin in CTNNB1-mutated endometrial cancer

Mol Carcinog. 2021 Aug;60(8):511-523. doi: 10.1002/mc.23308. Epub 2021 May 26.


The role of β-catenin/TCF transcriptional activity in endometrial cancer (EC) recurrence is not well understood. We assessed the impact of Wnt/β-catenin inhibition in EC models. In an analysis of the Cancer Genome Atlas, we confirmed that CTNNB1 mutations are enriched in recurrent low-risk EC and showed that aberrant Wnt/β-catenin pathway activation is associated with recurrence. We studied CTNNB1-wildtype (HEC1B, Ishikawa) and CTNNB1-mutant (HEC108, HEC265, HEC1B-S33Y, Ishikawa-S33Y) EC cell lines. Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). XAV939, Wnt-C59 and PyrPam inhibited function upstream of β-catenin transcriptional activity and were ineffective at inhibiting cell viability. In contrast, PRI724 and SM04690 indirectly inhibited β-catenin transcriptional activity and significantly reduced cell viability in CTNNB1-mutant cell lines. Treatment with SM04690 reduced cell viability (Licor Cell stain) in all EC cell lines, but viability was significantly lower in CTNNB1-mutant cell lines (p < 0.01). Mechanistically, SM04690 significantly inhibited proliferation measured via 5'-bromo-2'-deoxyuridine incorporation and reduced T cell factor (TCF) transcriptional activity. HEC1B, HEC1B-S33Y and HEC265 tumor-bearing mice were treated with vehicle or SM04690. Tumors treated with SM04690 had smaller mean volumes than those treated with vehicle (p < 0.001, p = 0.014, p = 0.06). In HEC1B-S33Y and HEC265 tumors, SM04690 treatment significantly reduced Ki67 H-scores compared to vehicle (p = 0.035, p = 0.024). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1-mutant EC.

Trial registration: NCT03355066.

Keywords: CTNNB1; Wnt/β-Catenin; endometrial cancer; small molecule agents; tumor suppressor.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cell Survival
  • Disease Management
  • Disease Susceptibility
  • Endometrial Neoplasms / drug therapy
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / metabolism*
  • Endometrial Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Indazoles / pharmacology
  • Molecular Targeted Therapy
  • Mutation*
  • Pyridines / pharmacology
  • Recurrence
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • CTNNB1 protein, human
  • Heterocyclic Compounds, 3-Ring
  • Imidazoles
  • Indazoles
  • Pyridines
  • Wnt Proteins
  • XAV939
  • beta Catenin
  • lorecivivint

Associated data