Understanding the Molecular Mechanisms of SORBS2 in TNBC Lung Metastasis

Abstract

Metastasis is the leading cause of recurrence and mortality in triple-negative breast cancer (TNBC), an aggressive subtype that predominantly spreads to the lungs, brain, bones, and liver, with lung metastasis being particularly prevalent. Despite the clinical significance of TNBC metastasis, the molecular mechanisms that drive lung-specific metastasis remain poorly understood. RNA-binding proteins (RBPs) are crucial regulators of post-transcriptional gene expression and are frequently dysregulated in cancers. This study identifies SORBS2 as a critical RBP implicated in TNBC lung metastasis. Using RNA sequencing (RNA-seq) and LACE-seq, we demonstrate that SORBS2 regulates a specific set of genes through direct binding to coding sequences (CDS), introns, and 3’ untranslated regions (UTRs), and its binding targets are linked to various pathways, including a possible association with Wnt/β-catenin signaling, among others. Functional assays confirm that SORBS2 knockdown inhibits proliferation, migration, and invasion in TNBC cells. These findings highlight SORBS2 as a key regulator of TNBC lung metastasis, with a context-dependent role that promotes metastatic behavior in highly metastatic TNBC cells, providing potential avenues for novel therapeutic strategies.