Abstract B15: Transforming growth factor β type III (TβRIII/Betaglycan) suppresses canonical Wnt signaling in ovarian cancer
Authors: Jenkins Laura M. , Varadaraj Archana , Flores Haley , Karthikeyan Mythreye 
Published: May 2016

Abstract
Ovarian cancer remains the deadliest gynecologic malignancy and the fifth leading cause of death from cancer in women[1]. Transforming growth factor β Type III (TβRIII/Betaglycan) receptor is a ubiquitously expressed co-receptor for the TGF-β ligand superfamily[2] whose expression is significantly decreased or lost in human epithelial ovarian tumors compared to normal tissue, with loss of TβRIII expression correlating with tumor grade and ovarian cancer progression[3]. TβRIII has increasing roles in suppressing cancer progression via cell motility[4], cell adhesion[5], and cell differentiation[2], largely independent of its TGF-β co-receptor functions[2, 3]. Structurally, TβRIII is a transmembrane proteoglycan containing both heparan sulfate and chondroitin sulfate glycosaminoglycan (GAG) chain modifications in its extracellular domain[5] that can interact with non-TGF-β family members, namely FGF2, via its GAG chains to regulate tumorigenesis[2].There is increasing evidence that Wnt glycoproteins that play complex roles in cancer[1, 6-11] have a high affinity for GAG chains on proteoglycans[12, 13]. Thus, we have initiated studies to determine the possible role of TβRIII on canonical Wnt3a signaling in ovarian cancer. Using a combination of cell signaling and biochemical approaches in ovarian cancer models, we find that TβRIII suppresses Wnt3a signaling by binding Wnt3a via its heparan sulfated GAG chains, which leads to perturbation of the LRP6/Frizzled/Wnt3a complex required for Wnt3a signaling activation. Reciprocal overexpression and knockdown of TβRIII in ovarian cancer cell lines reveal that TβRIII is a strong suppressor of canonical Wnt3a signaling, largely independent of TβRIII’s role as a TGF-β co-receptor. Finally, we provide evidence, via TCF/LEF-sensitive reporter activity[14], that TβRIII chondroitin sulfate chains can promote Wnt3a signaling in the absence of its heparan sulfate chains. These results indicate an intricate mode of Wnt3a signaling regulation by TβRIII/Betaglycan, mediated by distinct functions of its heparan and chondroitin chains. Our studies suggest a critical role for TβRIII’s heparan and chondroitin sulfated GAG modifications in modulating Wnt3a signaling and, more importantly, a possible therapeutic approach to address malfunctions in the Wnt signaling pathways that lead to ovarian carcinogenesis.
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Citation Format: Laura M. Jenkins, Archana Varadaraj, Haley Flores, Mythreye Karthikeyan. Transforming growth factor β type III (TβRIII/Betaglycan) suppresses canonical Wnt signaling in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B15.