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

The heparan sulfate proteoglycan syndecan-3 (SDC3) is a critical regulator of cell-matrix interactions. While other syndecan family members contribute 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 <i>TNM-plot</i>, <i>The Human Protein Atlas</i>, and <i>Kaplan-Meier Plotter</i>, 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 progression, cell migration, and 3D-spheroid-formation in MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, SDC3 depletion results in dysegulated gene expression of matrix metalloproteinases (<i>MMP1</i>, <i>MMP2</i>, <i>MMP9</i>) in MDA-MB-231 cells, and upregulation of E-cadherin (<i>CDH1</i>) and vascular endothelial growth factor A (<i>VEGFA</i>) in MCF-7 cells. Activation of proto-oncogene tyrosine-protein kinase Src was inhibited when SDC3 depletion was combined with tissue factor pathway inhibitor treatment. These findings demonstrate that breast cancer cell-derived SDC3 plays a pivotal role in tumor progression.