Abstract 423: Decipher the molecular mechanisms by which syndecan-1 in breast cancer stroma fibroblasts regulates extracellular matrix fiber organization and carcinoma cell motility

Abstract

Abstract The cell surface proteoglycan syndecan-1 (Sdc1) is frequently induced in the stromal fibroblasts of invasive breast carcinomas. We have recently identified a striking correlation between stromal Sdc1 expression and extracellular matrix (ECM) fiber architecture, both In vivo (in human breast carcinoma samples) and in vitro. Bioactive, cell-free 3D ECMs generated from cultures of Sdc1-positive human mammary fibroblasts (HMF), termed ECM-Sdc1, showed an organized, aligned fiber architecture, which contrasted markedly with the random fiber arrangement seen in the ECM of Sdc1-negative HMFs (ECM-mock). We further demonstrated that aligned ECM fiber architecture was responsible for the enhanced directional migration and invasion of the breast carcinoma cells when seeded into the fibroblast-free ECM-Sdc1. To decipher the molecular mechanisms responsible for the formation of an invasion-permissive ECM, a series of Sdc1 mutants was introduced into HMF. These include a heparan sulfate (HS) -deficient, a cytoplasmic domain (CD) deletion and a transmembrane domain (TMD) substitution mutant. Early experiments suggest that HS are required for the activity of Sdc1 in regulating ECM alignment, while TDM is dispensable. Integrins play a key role in the assembly of the provisional fibronectin-rich ECM and Sdc1 has been shown to be an important regulator of integrin activity. Therefore, we have begun to investigate the the role of integrins in Sdc1-mediated ECM fiber alignment. HMF expresses various integrins, as determined by Western blotting and flow cytometry. Using siRNA oligos, we are targeting different integrin subunits including α4, α5, αV and β3 to determine, which integrins are responsible for Sdc1-dependent ECM fiber alignment and consequently the invasion-permissive properties of the ECM. A better understanding of the mechanisms governing ECM organization may lead to the development of novel stroma-targeted therapy for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 423. doi:10.1158/1538-7445.AM2011-423