Heparan sulfate proteoglycans (HSPGs) act as signaling co-receptors by interaction of their sulfated glycosaminoglycan chains with numerous signaling molecules. In breast cancer, the function of heparan sulfate 2-O-sulfotransferase (HS2ST1), the enzyme mediating 2-O-sulfation of HS, is largely unknown. Hence, a comparative study on the functional consequences of HS2ST1 overexpression and siRNA knockdown was performed in the breast cancer cell lines MCF-7 and MDA-MB-231. HS2ST1 overexpression inhibited Matrigel invasion, while its knockdown reversed the phenotype. Likewise, cell motility and adhesion to fibronectin and laminin were affected by altered HS2ST1 expression. Phosphokinase array screening revealed a general decrease in signaling via multiple pathways. Fluorescent ligand binding studies revealed altered binding of fibroblast growth factor 2 (FGF-2) to HS2ST1-expressing cells compared with control cells. HS2ST1-overexpressing cells showed reduced MAPK signaling responses to FGF-2, and altered expression of epidermal growth factor receptor (EGFR), E-cadherin, Wnt-7a, and Tcf4. The increased viability of HS2ST1-depleted cells was reduced to control levels by pharmacological MAPK pathway inhibition. Moreover, MAPK inhibitors generated a phenocopy of the HS2ST1-dependent delay in scratch wound repair. In conclusion, HS2ST1 modulation of breast cancer cell invasiveness is a compound effect of altered E-cadherin and EGFR expression, leading to altered signaling via MAPK and additional pathways.
Bibliographic Metadata
Bibliographic Metadata
- TitleHS2ST1-dependent signaling pathways determine breast cancer cell viability, matrix interactions, and invasive behavior
- AuthorKumar, Archana Vijaya ; Brézillon, Stéphane ; Untereiner, Valérie ; Sockalingum, Ganesh Dhruvananda ; Katakam, Sampath Kumar ; Mohamed, Hossam Taha ; Kemper, Björn ; Greve, Burkhard ; Mohr, Benedikt ; Ibrahim, Sherif ; Goycoolea, Francisco Martin ; Kiesel, Ludwig ; Pavão, Mauro S. G. ; Motta, Juliana M. ; Götte, Martin
- Published
- AnnotationFinanziert über die DEAL-Vereinbarung mit Wiley 2019-2022.
- LanguageEnglish
- Bibl. ReferenceCancer Science 111 (2020) 8, 2907-2922
- Document typeJournal Article
- Keywords (EN)
- URN
- DOI
Restriction-Information
- The document is publicly available on the WWW
Links
- Social MediaShare
- Reference
- IIIF
Files
Classification
Abstract
Stats
- The PDF-Document has been downloaded 1 times.
License/Rightsstatement