Deregulation of the non‐canonical pathway in triple‐negative breast cancer

Abstract

Planar cell polarity (PCP) is controlled by a non‐canonical Wnt pathway. It organizes the polarization of many epithelial tissues and organs within the plane, and drives cell migration and cell intercalation of non‐epithelial cells such as mesenchymal cells. Loss of function of PCP genes can lead to severe neural tube defects in animal models and human. Little is known about the role of PCP genes in tumor growth and dissemination.A screen led us to identify Vangl2, a PCP receptor, as a molecule overexpressed at the genomic, transcriptomic and protein levels in poor prognosis triple negative breast cancers. Using cultured breast cancer cells, we show that Vangl2 is implicated in tumorigenicity and cell migration, and triggers a non‐canonical Wnt‐JNK pathway. Implication of Vangl2 in tumor growth was confirmed in xenograft assays in nude mice. Through a combinatory two‐hybrid/proteomic approach, we further discovered Vangl2 PDZ partners including Scribble and Dishevelled. Interaction with Scribble, but not Dishevelled, is required for cell migration of cancer cells. Our work reveals a novel implication for PCP proteins in triple negative breast cancer.