Abstract
Receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is expressed during embryogenesis and by certain leukemias, but not by normal adult tissues. Here we show that the neoplastic cells of many human breast cancers express the ROR1 protein and high-level expression of ROR1 in breast adenocarcinoma was associated with aggressive disease. Silencing expression of ROR1 in human breast cancer cell lines found to express this protein impaired their growth in vitro and also in immune-deficient mice. We found that ROR1 could interact with casein kinase 1 epsilon (CK1ε) to activate phosphoinositide 3-kinase-mediated AKT phosphorylation and cAMP-response-element-binding protein (CREB), which was associated with enhanced tumor-cell growth. Wnt5a, a ligand of ROR1, could induce ROR1-dependent signaling and enhance cell growth. This study demonstrates that ROR1 is expressed in human breast cancers and has biological and clinical significance, indicating that it may be a potential target for breast cancer therapy.
Highlights
The receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) was identified by a polymerase chain reaction (PCR)-based search for tyrosine kinases similar to the tropomyocin receptor kinase (Trk) neurotropic receptors [1]
Our results reveal that human breast cancers express ROR1, which can contribute to tumor-cell growth and survival via activation of phosphoinositol kinase (PI3K), AKT, and cAMP-response-element-binding protein (CREB)
We present data demonstrating that high proportions of human breast cancers expressed ROR1
Summary
The receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) was identified by a polymerase chain reaction (PCR)-based search for tyrosine kinases similar to the tropomyocin receptor kinase (Trk) neurotropic receptors [1]. ROR1 and a related protein, ROR2, were identified as orphan receptors with an extracellular Frizzled-like, cysteine-rich domain, an extracellular, membraneproximal kringle domain, and an intracellular tyrosine-kinase-like domain [2]. Both ROR proteins are evolutionarily conserved among different species [1,2,3,4,5]. We and others found that ROR1 was expressed by leukemia cells and some cancer cell lines, and was involved in cell survival [10,12,13,14,15,16,17,18]. Our results reveal that human breast cancers express ROR1, which can contribute to tumor-cell growth and survival via activation of PI3K, AKT, and CREB
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