Chondroitin Sulfate-E Is a Negative Regulator of a Pro-Tumorigenic Wnt-Beta-Catenin-Collagen 1 Axis in Breast Cancer CellsReport as inadecuate




Chondroitin Sulfate-E Is a Negative Regulator of a Pro-Tumorigenic Wnt-Beta-Catenin-Collagen 1 Axis in Breast Cancer Cells - Download this document for free, or read online. Document in PDF available to download.

Expression of the glycosaminoglycan chondroitin sulfate-E CS-E is misregulated in many human cancers, including breast cancer. Cell-surface associated CS-E has been shown to have pro-tumorigenic functions, and pharmacological treatment with exogenous CS-E has been proposed to interfere with tumor progression mediated by endogenous CS-E. However, the effects of exogenous CS-E on breast cancer cell behavior, and the molecular mechanisms deployed by CS-E are not well understood. We show here that treatment with CS-E, but not other chondroitin forms, could interfere with the invasive protrusion formation and migration of breast cancer cells in three-dimensional organotypic cultures. Microarray analysis identified transcriptional programs controlled by CS-E in these cells. Importantly, negative regulation of the pro-metastatic extracellular matrix gene Col1a1 was required for the anti-migratory effects of exogenous CS-E. Knock-down of Col1a1 gene expression mimics the effects of CS-E treatment, while exposing cells to a preformed collagen I matrix interfered with the anti-migratory effects of CS-E. In addition, CS-E specifically interfered with Wnt-beta-catenin signaling, a known pro-tumorigenic pathway. Lastly, we demonstrate that Col1a1 is a positively regulated target gene of the Wnt-beta-catenin pathway in breast cancer cells. Together, our data identify treatment with exogenous CS-E as negative regulatory mechanism of breast cancer cell motility through interference with a pro-tumorigenic Wnt-beta-catenin - Collagen I axis.



Author: Catherine M. Willis, Michael Klüppel

Source: http://plos.srce.hr/



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