Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes
Authors:
- Eyyad NassarENEyyad Nassar
- Nourhan HassanNourhan Hassan
- Eslam A. El-GhonaimyEEEslam A. El-Ghonaimy
- Hebatallah HassanHHHebatallah Hassan
- Mahmoud Salah AbdullahMAMahmoud Salah Abdullah
- Theresa V. RottkeTRTheresa V. Rottke
- Ludwig KieselLudwig Kiesel
- Burkhard GreveBGBurkhard Greve
- Sherif Abdelaziz IbrahimSISherif Abdelaziz Ibrahim
- Martin GötteMartin Götte
Open Access
Abstract
Triple-negative breast cancer (TNBC) is characterized by increased angiogenesis, metastasis, and poor survival. Dysregulation of the cell surface heparan sulfate proteoglycan and signaling co-receptor Syndecan-1 is linked to poor prognosis. To study its role in angiogenesis, we silenced Syndecan-1 in TNBC cell lines using a 3D human umbilical vein endothelial cell (HUVEC) co-culture system. Syndecan-1 siRNA depletion in SUM-149, MDA-MB-468, and MDA-MB-231 cells decreased HUVEC tubule network formation. Angiogenesis array revealed reduced VEGF-A and tissue factor (TF) in the Syndecan-1-silenced secretome. qPCR independently confirmed altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in SUM-149, MDA-MB-231, and MDA-MB-468 cells. ELISA revealed reduced secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) upon Syndecan-1 depletion, while TF pathway inhibitor treatment impaired angiogenesis. Survival analysis of 3951 patients demonstrated that high expression of F3 and F7 are associated with better relapse-free survival, whereas poor survival was observed in TNBC and p53 mutant basal breast cancer (F3) and in ER-negative and HER2-positive breast cancer (F2R, F2RL1). STRING protein network analysis revealed associations of Syndecan-1 with VEGF-A and IGFBP1, further associated with the TF and ET-1 pathways. Our study suggests that TNBC Syndecan-1 regulates angiogenesis via the TF and additional angiogenic pathways and marks its constituents as novel prognostic markers and therapeutic targets.Keywords
Funding Information
- Horizon 2020 Framework Programme (MSCA-RISE no. 645756 GLYCANC)
- Westfälische Wilhelms-Universität Münster (Open Access Publishing Fund)
- Konrad-Adenauer-Stiftung (Stipendium Eyyad Nassar)
- Deutscher Akademischer Austausch Dienst Kairo (GERLS Grant 91664677)
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