A truncated TNS3 isoform expressed in metastatic triple negative breast cancer stabilizes FAK and promotes lung metastasis.

Triple-negative breast cancer (TNBC), particularly in metastatic cases, lacks effective therapeutic vulnerabilities. We previously identified TNS3-S as a variant of TNS3 that is selectively expressed in TNBC. Here, we show that TNS3-S expression is regulated by TGFβ signaling and CpG methylation at its regulatory region. Notably, TNS3-S expression is markedly elevated in lung-metastasized TNBC tumors compared to primary tumors. Knockout of TNS3-S suppressed lung metastasis and rendered the cells sensitive to anoikis, both of which were reversed by rescued expression of TNS3-S. Mechanistically, TNS3-S stabilizes focal adhesion kinase, thereby facilitating adhesion-mediated proliferative signaling. Exploratory analyses of TCGA cohorts suggested that reduced promoter CpG methylation correlates with increased TNS3-S expression and could be associated with poorer outcomes across several cancer types. Collectively, these findings identify TNS3-S as a metastasis-associated regulator that promotes tumor outgrowth in distant organs and raise the possibility that epigenetic de-repression contributes to its activation during disease progression.