The CDC42-interacting protein 4 controls epithelial cell cohesion and tumor dissemination

The role of endocytic proteins and the molecular mechanisms underlying epithelial cell cohesion and tumor dissemination are not well understood. Here, we report that the endocytic F-BARcontaining CDC42-interacting protein 4 (CIP4) is upregulated in ERBB2-positive human breast cancer (BC), correlates with increased distant metastasis, and is an independent predictor of poor disease outcome in subsets of BC patients. Consistently, CIP4 is required for ERBB2- and TGF-ß1- induced cell scattering, motility and invasion into 3D matrices by BC lines and for the conversion from ductal breast carcinoma in situ to invasive carcinoma in mouse xenograft models. In normal and tumorigenic derivatives of MCF10A breast epithelial cells, depletion of CIP4 induces cell compaction and impairs EGF-induced cell scattering, motility and invasion. These defects are not due to altered EGFR signaling or trafficking, but to impaired EGF-induced E-cadherin endocytosis and actomyosin contractility, which is required to generate tangential forces to break cell-cell junctions. At the molecular level, CIP4 promotes the formation of an E-cadherin-CIP4-SRC complex that controls SRC activation, E-cadherin endocytosis and localized phosphorylation of the myosin light chain kinase. Thus, CIP4 critically controls cell-cell cohesion and is required for the acquisition of an invasive phenotype in breast tumors.