Puvirajesinghe TM, Bertucci F, Jain A, Scerbo P, Belotti E, Audebert S, Sebbagh M, Lopez M, Brech A, Finetti P, Charafe-Jauffret E, Chaffanet M, Castellano R, Restouin A, Marchetto S, Collette Y, Gonçalvès A, Macara I, Birnbaum D, Kodjabachian L, Johansen T, Borg JP
Nat Commun. 2016 7
· PMCID: PMC4729931
The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2-p62/SQSTM1-JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2-p62/SQSTM1 interaction. VANGL2-JNK signalling is thus a potential target for breast cancer therapy.
MeSH Terms (30)Adaptor Proteins, Signal Transducing Animals Blotting, Western Breast Neoplasms Carcinoma, Ductal, Breast Carcinoma, Lobular Cell Line, Tumor Cell Migration Assays Cell Movement Cell Polarity Cell Proliferation DNA Copy Number Variations Embryo, Nonmammalian Female Humans Immunoprecipitation Intracellular Signaling Peptides and Proteins MAP Kinase Signaling System Mass Spectrometry Membrane Proteins Mice Microscopy, Electron Middle Aged Neoplasm Transplantation Prognosis Proportional Hazards Models RNA, Messenger Sequestosome-1 Protein Wnt Signaling Pathway Xenopus