The heparan sulfate proteoglycan Syndecan-1 (CD138) regulates tumor progression in a 3D model of ductal carcinoma in situ of the breast

Ductal carcinoma in situ (DCIS) is a form of breast cancer that is restricted to the lactiferous ducts and has not yet invaded the surrounding breast tissue. Dysregulation of the transmembrane heparan sulfate proteoglycan Syndecan-1 (Sdc-1) plays a role in tumour progression of invasive breast cancer (IBC). In this study, we employed an siRNAnockdown approach in the DCIS model cell line MCF10A.DCIS.com to investigate a potential connection between Sdc-1 and epithelial mesenchymal transition (EMT), proteolysis and the Rho kinase (ROCK) pathway.

The impact of Sdc-1-depletion on the cellular phenotype was investigated in a Matrigel-based 3D cell culture model, while its effect on the gene expression of several EMT- and proteolysis-markers was evaluated via qPCR with and without ROCKinhibitors. elated to the TNMPlot-database and verified via String analysis.

Analysis of gene expression data of the TNMPlot-database revealed that Sdc-1 expression was higher in primary breast tumors compared to metastases. Sdc-1 depletion resulted in the formation of larger spheroids and the formation of invasive protrusions. Application of matrix metalloproteinase (MMP) and Rho kinase inhibitors could block the Sdc-1-induced phenotype. qPCR analysis of Sdc-1-depleted cells in 2D culture revealed altered expression of the EMT-markers CDH1, FN-1, CLDN1, VIM, the proteolysis markers MMP2, MMP3, and MMP9, HPSE, as well as ROCK-2. String analysis confirmed an interaction of the investigated gene products at the protein level.

Our results suggest that diminished Sdc-1 expression plays a role in DCIS progression to IBC through deregulation of proteolytic factors and a partial EMT.

Publication History

Article published online:
21 June 2022