The GLYCANC project is coordinated by Prof. Dr. Martin Götte at the University of Münster, Germany (WWU). The research group of Prof. Dr. Götte has a long-standing interest in analysing the molecular role of proteoglycans and glycosaminoglycans in the pathogenesis of malignant and inflammatory diseases. In previous work, we could demonstrate that dysregulated expression of the heparan sulfate proteoglycan Syndecan-1 is of predictive value for the outcome of neoadjuvant chemotherapy of breast cancer, and that its expression is associated with angiogenesis and lymphangiogenesis in early stages of breast cancer. Using in vitro overexpression and siRNA knockdown and microRNA transfection approaches assisted by Affymetrix gene array technology in human breast cancer cell lines, we demonstrated that Syndecan-1 is a novel target of prometastatic microRNAs, and that dysregulation of Syndecan-1 affects numerous molecular processes contributing to breast cancer pathogenesis (see Figure). Heparan-sulfate dependent modulation of multiple receptor tyrosine kinase signalling as well as integrin-dependent pathways, dysregulated expression of homotypic cell adhesion molecules and altered expression and activity of MMPs were identified as molecular aspects of Syndecan-1 function in the pathogenesis and progression of breast cancer. Using a complementary ectopic expression approach of enzymes involved in heparan sulfate biosynthesis, we could identify a specific role for 3-O-sulfated heparan sulfate residues in mediating breast cancer cell invasiveness via modulation of a TCF4-dependent signal transduction pathway. A similar experimental approach revealed that 6-O-sulfated heparan sulfate residues may affect the invasive behaviour of aggressive breast cancer cell lines via a different molecular mechanism, which is currently being explored.&nb
Former clinic for gynecology (Picture courtesy of Prof. S. Kliesch)
Our most recent activities aim at deciphering a role for heparin sulfate proteoglycans as modulators of a cancer stem cell phenotype, which is considered a major mechanism in conferring therapeutic resistance and recurrence in numerous tumor entities. Within the GLYCANC project, WWU will provide expertise in cancer cell biology, functional microRNA analysis and the analysis of a cancer stem cell function to the consortium.
Figure: Role of the heparan sulfate proteoglycan Syndecan-1 in breast cancer pathogenesis. Top left: Syndecan-1 expression is dysregulated in breast cancer (Immunohistochemistry on breast cancer tissue). Top right: Immunofluorescence microscopy reveals localization of a non-sheddable mutant form of Syndecan-1 (green) to focal adhesions (red actin staining). Bottom: Posttranscriptional regulation of Syndecan-1 expression by microRNA miR-10b has an impact on breast cancer cell motility and invasiveness via modulation of integrin-associated signaling pathways. See key publications for details.

Key publications

Ibrahim SA et al. MicroRNA regulation of proteoglycan function in cancer. FEBS J. 2014, 281:5009-22.

Vijaya Kumar A et al. HS3ST2 modulates breast cancer cell invasiveness via MAP kinase- and Tcf4 (Tcf7l2)-dependent regulation of protease and cadherin expression. Int J Cancer. 2014, 135:2579-92.

Ibrahim SA et al. MicroRNA-dependent targeting of the extracellular matrix as a mechanism of regulating cell behavior. Biochim Biophys Acta. 2014, 1840:2609-20.

Hassan H et al. Syndecan-1 modulates β-integrin-dependent and interleukin-6-dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation. FEBS J. 2013;280:2216-27.

Ibrahim SA et al. Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling. PLoS One. 2013;8:e85737

Ibrahim SA et al. Targeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motility and invasiveness via a Rho-GTPase- and E-cadherin-dependent mechanism. Int J Cancer. 2012;131:E884-96.

Nikolova V, et al. Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression. Carcinogenesis. 2009;30:397-407.