Wnt5a induces ROR1 to recruit cortactin to promote breast-cancer migration and metastasis

Md Kamrul Hasan; George F Widhopf 2nd; Suping Zhang; Sharon M Lam; Zhouxin Shen; Steven P Briggs; Barbara A Parker; Thomas J Kipps

doi:10.1038/s41523-019-0131-9

Wnt5a induces ROR1 to recruit cortactin to promote breast-cancer migration and metastasis

NPJ Breast Cancer. 2019 Oct 25:5:35. doi: 10.1038/s41523-019-0131-9. eCollection 2019.

Authors

Md Kamrul Hasan¹, George F Widhopf 2nd¹, Suping Zhang^{1

2}, Sharon M Lam¹, Zhouxin Shen³, Steven P Briggs³, Barbara A Parker¹, Thomas J Kipps^{1

2}

Affiliations

¹ 1Moores Cancer Center, University of California San Diego, La Jolla, CA USA.
² Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518060 Guangdong China.
³ 3Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA USA.

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.

Keywords: Breast cancer; Metastasis; RHO signalling.

Grants and funding

R01 CA236361/CA/NCI NIH HHS/United States