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

Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. In order to understand the molecular basis of these observations, we overexpressed ROR2 in human breast cancer cell lines and characterized them by RNA-Sequencing. High levels of ROR2 were associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. Using gene expression analysis we demonstrated an upregulation of several non-canonical WNT ligands in ROR2-overexpressing breast cancer cells, in particular WNT11. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. Taken together, our studies revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligands, e.g. WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis. Human breast cancer cells (MCF-7, SK-BR-3 and BT-474) were transfected either with an empty vector (pcDNA) or with a hROR2 overexpression plasmid (pROR2). To gain further insight into additional pathways regulated specifically by ROR2/WNT11, we characterized ROR2-overexpressing MCF-7 cells with siRNA-mediated WNT11 knockdown by RNA-Seq.