Abstract
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.
Highlights
Breast cancer is one of the most commonly diagnosed and most invasive cancers in women, and it is the second leading cause of death in women in the U.S [1]
Our data demonstrate that chondroitin sulfate-E (CS-E) could negatively regulate Col1a1 gene expression through inhibition of Wnt/betacatenin signaling, which in turn led to decreased breast cancer cell motility
To get an initial understanding of the potential roles of the differentially sulfated chondroitin sulfate (CS) molecules in breast cancer cells, we set out to characterize the effects of treatment with exogenous C4S, C6S, CS-D and CS-E on EMT6 cells grown in a well-established organotypic three dimensional (3D) on-top Matrigel assay (Figure 1) [31]
Summary
Breast cancer is one of the most commonly diagnosed and most invasive cancers in women, and it is the second leading cause of death in women in the U.S [1]. Targeting molecules of the tumor microenvironment has become an active area of research for cancer treatment [2,3,4]. One component of the tumor microenvironment is the glycosaminoglycan chondroitin sulfate (CS). CS biosynthesis and sulfation balance is tightly controlled and of critical importance in development and disease [5,6,7,8,9,10,11,12,13,14]. Cell typespecific sulfation balance is influenced by growth factor signaling and in turn can control cellular signaling pathways [7,8,9,10,11,13,14]. The specific sulfation pattern of CS chains dictates its function and binding affinities [7,9,15]
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