CD73 restrains mutant β-catenin oncogenic activity in endometrial carcinomas

Abstract

Missense mutations in exon 3 of CTNNB1, the gene encoding {beta}-catenin, are associated with poor outcomes in endometrial carcinomas (EC). Clinically, CTNNB1 mutation status has been difficult to use as a predictive biomarker as {beta}-catenin oncogenic activity is modified by other factors, and these determinants are unknown. Here we reveal that CD73 restrains the oncogenic activity of exon 3 {beta}-catenin mutants, and its loss associates with recurrence. Using 7 patient-specific mutants, with genetic deletion or ectopic expression of CD73, we show that CD73 loss increases {beta}-catenin-TCF/LEF transcriptional activity. In cells lacking CD73, membrane levels of mutant {beta}-catenin decreased which corresponded with increased levels of nuclear and chromatin-bound mutant {beta}-catenin. These results suggest CD73 sequesters mutant {beta}-catenin to the membrane to limit its oncogenic activity. Adenosine A1 receptor deletion phenocopied increased {beta}-catenin-TCF/LEF activity seen with NT5E deletion, suggesting that the effect of CD73 loss on mutant {beta}-catenin is mediated via attenuation of adenosine receptor signaling. RNA-seq analyses revealed that NT5E deletion alone drives pro-tumor Wnt/{beta}-catenin gene expression and, with CD73 loss, {beta}-catenin mutants dysregulate zinc-finger and non-coding RNA gene expression. We identify CD73 as a novel regulator of oncogenic {beta}-catenin and help explain variability in patient outcomes in CTNNB1 mutant EC. O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/624183v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@f8e8f0org.highwire.dtl.DTLVardef@184e92aorg.highwire.dtl.DTLVardef@e7cb55org.highwire.dtl.DTLVardef@1d6421e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG