Classic Protocadherin PCDH10 Functions as a Tumor Suppressive Scaffold Protein Antagonizing Oncogenic WNT/β-catenin Signaling in Breast Carcinogenesis

Epigenetic mechanisms, including DNA methylation, frequently inactivate tumor suppressor genes (TSGs) in multiple tumorigeneses. This study investigated the molecular basis of the tumor-suppressive role of the classic protocadherin tumor suppressor <i>PCDH10</i> in breast carcinogenesis. Frequent <i>PCDH10</i> downregulation and promoter methylation was identified in breast cancer, correlating with poor prognosis and ER-negative status. Restoration of <i>PCDH10</i> expression significantly suppressed tumorigenesis both <i>in vitro</i> and <i>in vivo,</i> by inhibiting epithelial-mesenchymal transition (EMT) and cancer stemness. RNA sequencing revealed <i>PCDH10</i>'s role in Wnt/β-catenin signaling suppression. Mechanistically, PCDH10 enhanced GSK-3β phosphorylation at Try216, inhibited aberrant β-catenin activation and upregulated the expression of the tumor-suppressive nuclear envelope protein LMNA expression through direct binding. Concurrently, it also attenuated other oncogenic signaling <i>via</i> suppression of RhoA and Akt phosphorylation. Collectively, promoter CpG methylation-mediated silencing of <i>PCDH10</i> promotes breast cancer progression. <i>PCDH10</i> restoration antagonizes tumorigenesis by dual blockade of Wnt/β-catenin and Akt signaling pathways through interactions with GSK-3β, β-catenin, and LMNA, as a scaffold protein. Our findings reveal a novel <i>PCDH10</i>-dependent tumor-suppressive axis and highlight its potential as a therapeutic target and biomarker in breast cancer.