Differential Localization of β-Catenin Protein in CTNNB1 Mutant Endometrial Cancers Results in Distinct Transcriptional Profiles

CTNNB1 exon 3 mutation is a well-established driver of nearly 30% of endometrioid endometrial cancers (EECs), and this is associated with worse patient survival. Paradoxically, we have previously demonstrated that mutant β-catenin protein does not robustly localize to the nucleus in these cancers. The purpose of this study was to determine downstream gene expression in these cancers with nuclear or membrane/cytoplasmic mutant β-catenin protein localization. Spatial transcriptomics was performed on tumors with intratumor nuclear and nonnuclear mutant β-catenin, using the protein localization to select for regions of interest (ROIs). Differential expression analysis of all nuclear and nonnuclear ROIs yielded distinct transcriptional profiles based on the localization of β-catenin. Analysis revealed enrichment for Wnt signaling and epithelial-to-mesenchymal transition pathways in nuclear ROIs and hormone signaling in nonnuclear ROIs. Hierarchical clustering yielded 2 clusters comprised of almost entirely nuclear or nonnuclear ROIs. A novel therapeutic target, TROP2, encoded by the TACSTD2 gene, was identified to be altered by Wnt/β-catenin signaling. These data provide evidence for highly heterogeneous intratumor transcriptional profiles dependent on β-catenin protein localization in EEC with CTNNB1 driver mutations. Therefore, reporting of β-catenin immunohistochemistry should include an estimated percentage of tumor with nuclear localization in EEC tumors with exon 3 CTNNB1 mutations.