Syndecan-1 and -4 influence Wnt signaling and cell migration in human breast cancers

Heparan sulfate proteoglycans (HSPGs) participate in numerous normal and pathophysiological cellular functions. HSPGs are crucial components of the extracellular matrix (ECM) binding signalling molecules such as fibroblast growth factors (FGF) and Wnts to mediate various cellular processes including cell proliferation, migration, and cancer invasion. The syndecans (SDCs1-4) are a major family of four HSPGs, implicated in the development of breast carcinomas. This study examined syndecan-1 (SDC1) and syndecan-4 (SDC4; SDC1/4) in breast cancer (BC) in vitro cell models and their role in tumorigenesis. Gene expression of HSPG core proteins, biosynthesis and modification enzymes along with Wnt/FGF morphogen pathway components were examined following inhibition of SDC1 and SDC4 via small interfering RNA (siRNA), and enhancement of HSPGs via addition of heparin and FGF. siRNAs knockdowns (KDs) were performed in the MCF-7 (lowly invasive and poorly metastatic) and the MDA-MB-231 (highly invasive and metastatic) human BC cell lines. Significantly decreased gene expression of SDC1 and SDC4 was observed in both cell lines following KD. Additionally, via gene expression analysis, downregulation of SDC1/4 decreased the biosynthesis of heparan sulfate modification enzymes and reduced expression of Wnt signalling molecules. Following the enhancement/inhibition of HSPGs via heparin/siRNA treatment, heparin increased the migratory characteristics of MCF-7 cells while KD of SDC1 increased cell migration in both MCF-7 and MDA-MB-231 cells when compared to scramble negative control conditions. Our findings suggest that a niche-specific function exists for SDC1/4 in the BC microenvironment, mediating Wnt signalling cascades and potentially regulating migration of BC cells.