Syndecan-1 (CD138) modulates breast cancer stem cell properties via regulation of IL-6-mediated STAT3 signaling

Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally induced tumorigenesis has been linked to an alteration in Wnt-responsive precursor cell pools suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. In this study, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human MDA-MB-231 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown substantially reduces putative cancer stem cell pools compared to controls. Moreover, the CD44(+)CD24(-/low) phenotype decreased upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated in Syndecan-1-silenced cells. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced in Syndecan-1-depleted cells compared to controls. As Syndecan-1 modulates the breast cancer stem cell phenotype via regulation of the IL-6/STAT3 and Wnt signaling pathways, it emerges as a promising novel target for therapeutic approaches.