The Wnt signaling pathway is involved in the development and progression of many human cancers, yet attempts to target the pathway therapeutically have been disappointing to date. The recent discovery that the ROR2 receptor tyrosine kinase (RTK) is a novel Wnt receptor provides the potential to target the non-canonical Wnt pathway for cancer treatments. As a member of the RTK superfamily of surface receptors ROR2 appears to possess dual roles as a tumor suppressor or activator depending on tumor type. This review will explore the dual role of ROR2 in tumorigenesis and provide an up to date analysis of current literature in this rapidly expanding field. Wnt Signaling PathwayWnt signaling is essential for embryonic development and cellular processes including differentiation, polarity, migration, invasion, adhesion and survival.1 These same cellular processes are crucial components of tumorigenesis and metastasis, and hence therapeutic strategies to target Wnt signaling in human cancer are increasingly being investigated. Deregulation of the Wnt signaling pathway has been implicated in numerous cancers including colorectal, breast, ovarian, and prostate cancer (reviewed in Ref. Non-canonical Wnt signaling has been less clearly characterized than canonical signaling. It encompasses at least two different signaling pathways-the Wnt/Ca 2þ pathway involving CaMKII, Protein-kinase-C (PKC) and NFAT, and the planar-cell polarity (PCP) pathway thought to signal through RhoA, Rac and c-Jun N-terminal kinase (Jnk). Importantly, the non-canonical Wnt signaling pathway has been shown to antagonise canonical Wnt signaling (Fig. 1). This observation has raised the possibility that activating the non-canonical Wnt pathway in cancers driven by hyperactivated canonical Wnt signaling may be a novel therapeutic approach. [3][4][5] Traditionally, the two arms of the pathway were defined by the specific Wnt ligand involved in activating the pathway. For example, Wnt1 and Wnt3a were thought to activate the canonical pathway, and Wnt5a and Wnt11 were thought to activate the non-canonical pathway. However, therapy targeted at the ligand level is unlikely to be successful, as studies have shown that in specific contexts, a number of the noncanonical Wnt ligands, particularly the prototypical non-canonical effector ligand Wnt5a, are also capable of initiating canonical Wnt signaling.6,7 Furthermore, the key canonical Wnt ligand, Wnt3a was recently shown to be capable of activating PKC, a non-canonical target. 8 These findings provide new insights into the pathway and throw into question the traditional ligand-mediated model of Wnt signaling. 9,10 A new paradigm is emerging within the Wnt field whereby the specific signaling pathway is not determined by the intrinsic properties of a particular Wnt ligand, but rather by the receptor configuration on the surface of a given cell. 10The ROR Family of Receptor Tyrosine KinasesThe two members that belong to the ROR family of receptor tyrosine kinases (RTKs) were originally referred to as orphan

This is the first study to report the expression of ROR2 in breast cancer. Breast cancer patients expressing ROR2 had a significantly worse prognosis than those lacking ROR2. ROR2 may regulate both β-catenin-dependent and β-catenin-independent Wnt signalling pathways, and represents a potential diagnostic and therapeutic target.