CD73 restrains mutant β-catenin oncogenic activity in endometrial carcinomas

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Missense mutations in exon 3 of the CTNNB1 gene, encoding β-catenin, are linked to poor outcomes in endometrial carcinomas (EC).
• CTNNB1 mutation status is an unreliable predictive biomarker due to unknown factors modifying β-catenin's oncogenic activity.

Purpose of the Study:

• To identify novel determinants of β-catenin oncogenic activity in endometrial cancer.
• To investigate the role of CD73 in regulating mutant β-catenin and its association with patient outcomes.

Main Methods:

• Utilized 7 patient-specific β-catenin mutants with genetic deletion or ectopic expression of CD73.
• Assessed β-catenin-TCF/LEF transcriptional activity, membrane and nuclear/chromatin-bound β-catenin levels.
• Performed adenosine A1 receptor deletion and RNA-sequencing (RNA-seq) analyses.

Main Results:

• CD73 loss significantly increased β-catenin-TCF/LEF transcriptional activity.
• Loss of CD73 led to decreased membrane and increased nuclear/chromatin-bound mutant β-catenin.
• Adenosine A1 receptor deletion mimicked the effects of NT5E (CD73) deletion, suggesting a role for adenosine signaling.
• NT5E deletion alone promoted Wnt/β-catenin gene expression; combined with CD73 loss, β-catenin mutants dysregulated zinc-finger and non-coding RNA expression.

Conclusions:

• CD73 acts as a novel suppressor of oncogenic β-catenin activity in endometrial cancer.
• CD73 loss is associated with increased tumor recurrence, potentially mediated by adenosine receptor signaling.
• Understanding CD73's role explains outcome variability in CTNNB1-mutant EC and suggests CD73 as a therapeutic target.