Co-mutations of CTNNB1 and PTEN Synergistically Promote EMT and Drive Aggressive Tumor Progression in Endometrial Cancer.

Co-mutations in PTEN and CTNNB1 are frequent and linked to poor prognosis, but their functional roles remain unclear. Using uterine-specific Pten knockout and stabilized β-catenin mutant mice (Pgrcre/+Ptenf/fCtnnb1f(ex3)/+; Ptend/dCtnnb1f(ex3)/+), we found markedly reduced survival, early-onset invasive adenocarcinoma, and aggressive metastatic disease compared to Pgrcre/+Ptenf/f; Ptend/d mice.

Transcriptomic and histopathological analyses revealed activation of oncogenic pathways (WNT/β-catenin, PI3K/AKT, Hedgehog, EMT), with loss of E-cadherin and upregulation of SNAIL confirming EMT. These findings show that PTEN–CTNNB1 co-mutations synergistically drive EMT and tumor progression, defining a distinct aggressive subtype of EEC.