The Role of the Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 In Breast Cancer Pathophysiology

The heparan sulfate proteoglycan syndecan-3 (SDC3) has emerged as a critical regulator of cell-matrix interactions. While other syndecan family members con-tribute to the progression of multiple cancers, SDC3's functional contributions to tumor biology remain largely unexplored. This study investigates the potential role of SDC3 in the pathogenesis of breast cancer. By conducting an in-silico analysis of publicly available datasets, including TNM-plot, The Human Protein Atlas, and Kaplan-Meier-Plotter, we observed that SDC3 is upregulated in breast cancer tissue. Notably, high SDC3 expression correlates with improved relapse-free survival in breast cancer patients. In vitro experiments revealed that SDC3 depletion significantly impairs cell viability, cell-cycle pro-gression, cell migration, and 3D-spheroid-formation in MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, SDC3 depletion results in multiple changes in gene expression, including upregulation of matrix metalloproteinases (MMP1, MMP9), downregulation of E-cadherin (CDH1), and altered levels of vascular endothelial growth factor A (VEGFA). At the protein level, changes in the activation of pro-to-oncogene tyrosine-protein kinase Src (SRC) are observed. These findings suggest that breast cancer cell-derived SDC3 plays a pivotal role in breast cancer progres-sion. In contrast, the positive prognostic value of SDC3 in breast tumors may point at a different role for SDC3 within the tumor micoenvironment.