WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer [patients]

Breast cancer is the most common cancer in women with more than two million new cases diagnosed in 2018. Patients frequently develop metastases in the course of their disease which limit survival due to the lack of a curative treatment. One signaling pathway that is frequently involved in cancer initiation and progression is the WNT pathway. Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. Here, we found the WNT receptor ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. In this study we addressed this question and demonstrated for the first time that WNT11 is a novel ligand for ROR2 in humans. WNT11 binds to the CRD of ROR2 and mediates WNT/PCP signaling via the RHO/ROCK pathway that confers an aggressive phenotype to breast cancer cells. ROR2 and WNT11 are both highly expressed in human brain metastases and linked with short patient survival. We collected samples from 31 patients with brain metastases and characterized them by RNA-Seq. With the obtained data, we performed a gene enrichment analysis looking at three different gene sets, either associated with canonical, non-canonical, or regulation of WNT signaling. Next, we isolated RNA from seven metastases as well as normal brain tissue and analysed the expression of ROR2 and its ligand WNT11 by quantitative real-time PCR. To confirm the role of ROR2/WNT11 in metastasis, we correlated the expression levels of ROR2 and WNT11 in the metastatic tissue with patient outcome using the gene expression data obtained by RNA-Seq.