ROR1 Is Expressed in Human Breast Cancer and Associated with Enhanced Tumor-Cell Growth

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.

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

“…Conversely, silencing ROR1, or treatment with an anti-ROR1 mAb, could enhance apoptosis, inhibit cell proliferation and migration/invasion, and reduce the capacity of tumor cells to develop metastatic foci (30,31,33). Similarly, silencing ROR1 could inhibit the capacity of primary ovarian cancer cells to form spheroids, invade ECM, or to develop tumor xenografts, which are functional characteristics associated with CSCs.…”

“…ROR1 is a type I orphan-receptor tyrosine kinase-like surface protein that is found on neoplastic cells of many different types of cancer, but not on normal adult tissues (26)(27)(28)(29)(30)(31)(32). Moreover, ROR1 predominately seems to be expressed by less well-differentiated tumors that have high potential for relapse and metastases and that also express markers associated with EMT (31,33). Conversely, silencing ROR1 in metastasis-prone breast-cancer cell lines could attenuate expression of genes associated with EMT and impair their migration/invasion capacity in vitro and their metastatic potential in vivo (33).…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…ROR2, for example, has been shown to activate phosphatidylinositol-3 kinase (PI3K), which in turn activates JNK and its associated transcription factors c-Jun and ATF2 in Xenopus [27,28]. Similarly, ROR1 activates the same signaling cascade to increase CREB phosphorylation in human breast cancer cells [29]. FZDs have been found to activate a number of additional intracellular effectors, including adenylate cyclase (AC), protein kinase A (PKA) and CREB [19], p38 and ATF2 [20] and Fyn and STAT3 [21].…”

WNT5A and Its Receptors in the Bone-Cancer Dialogue

“…2B, label 6). Thus, high expression of ROR1 was shown to be associated with increased tumor progression, (87) and highlights its potential as a treatment target. (88) Loss of WNT5A was exhibited to lead to shorter survival of patients with breast cancer.…”

“…Yes (127) Yes (128) Breast cancer (86,87) ; melanoma (92,94) ; non-small cell lung cancer (129) ; gastric cancer (130) ; ovarian cancer (131) …”