Abstract 3250: Chondroitin sulfate-mediated regulation of Wnt/β-catenin signaling in breast cancer

Abstract

Abstract Breast cancer is among the leading causes of cancer related deaths in women in the U.S. Aberrant activation of the Wnt/β-catenin signaling pathway plays a critical role in breast cancer progression; however, activating mutations in core pathway components are not frequently observed. Molecules that reside in the cellular microenvironment, including glycosaminoglycans, are known to regulate tumor progression. The glycosaminoglycan chondroitin sulfate, as part of proteoglycan molecules, resides at the cell surface or in the extracellular matrix, and has been proposed to regulate the activities of several signaling pathways. We show here that the balance of chondroitin sulfation is a critical regulator of Wnt/β-catenin signaling in breast cancer cells. Overexpression of the chondroitin sulfotransferase C4ST-1 in vitro can significantly reduce several parameters of Wnt/β-catenin signaling activity, including Wnt3a-stimulated total β-catenin levels, TOPFLASH reporter activity, and proliferation, suggesting that the specific chondroitin sulfation pattern conferred by C4ST-1 can negatively regulate Wnt/β-catenin signaling in breast cancer cells. Interestingly, we show that Wnt3a stimulation increases C4ST-1 mRNA and protein levels, thus forming a negative feedback loop to attenuate Wnt/β-catenin signaling output. Accordingly, treatment with the C4ST-1 product CS-E interferes with Wnt/β-catenin signaling activity, LRP6 phosphorylation, β-catenin nuclear localization, and Wnt3a-mediated biological events in vitro. These data identify a novel chondroitin sulfate-based control mechanism for the Wnt/β-catenin pathway, and provide evidence for a potential therapeutic use of CS-E as an inhibitor of Wnt/β-catenin signaling in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3250. doi:1538-7445.AM2012-3250