Abstract
ROR1 is a conserved oncoembryonic surface protein expressed in breast cancer. Here we report that ROR1 associates with cortactin in primary breast-cancer cells or in MCF7 transfected to express ROR1. Wnt5a also induced ROR1-dependent tyrosine phosphorylation of cortactin (Y421), which recruited ARHGEF1 to activate RhoA and promote breast-cancer-cell migration; such effects could be inhibited by cirmtuzumab, a humanized mAb specific for ROR1. Furthermore, treatment of mice bearing breast-cancer xenograft with cirmtuzumab inhibited cortactin phosphorylation in vivo and impaired metastatic development. We established that the proline at 841 of ROR1 was required for it to recruit cortactin and ARHGEF1, activate RhoA, and enhance breast-cancer-cell migration in vitro or development of metastases in vivo. Collectively, these studies demonstrate that the interaction of ROR1 with cortactin plays an important role in breast-cancer-cell migration and metastasis.
Highlights
ROR1 is an evolutionarily conserved, developmentally restricted type-I receptor–tyrosine-kinase-like orphan receptor,[1,2,3,4] which has a cytoplasmic domain consisting of a tyrosine-kinase-like domain, two serine/threonine-rich domains, and a proline-rich domain (PRD)
We did not detect such ROR1–cortactin complexes in lysates prepared from breastcancer–patient-derived xenografts (PDXs) cells cultured overnight in serum-free media unless they were treated with exogenous Wnt5a (Fig. 1f, g), suggesting
We found that Wnt5a induces ROR1 to associate with cortactin, which undergoes tyrosine phosphorylation in breast-cancer PDX cells or MCF7 cells transfected to express ROR1
Summary
ROR1 is an evolutionarily conserved, developmentally restricted type-I receptor–tyrosine-kinase-like orphan receptor,[1,2,3,4] which has a cytoplasmic domain consisting of a tyrosine-kinase-like domain, two serine/threonine-rich domains, and a proline-rich domain (PRD). We found that ROR1 is expressed by most human cancers, including breast cancer, intimating that it plays a role in cancer pathophysiology.[7] In support of this proposition are findings demonstrating that expression of ROR1 can enhance epithelial–mesenchymal transition and cancer-cell proliferation, migration, and metastasis.[8,9] high-level tumor-cell expression of ROR1 associates with adverse outcome in patients with various cancers.[8,10,11,12]. Amplification of the gene encoding cortactin is observed in at least 15% of metastatic breast carcinomas.[31,32] High-level breastcancer-cell expression and phosphorylation of cortactin associates with an unfavorable prognosis for patients with breast cancer.[33,34,35,36] In this study, we examined whether Wnt5a could stimulate ROR1 to complex with cortactin and thereby recruit and activate ARHGEF1 to enhance activation of RhoA and promote breastcancer-cell migration/metastasis
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