Abstract Planar cell polarity (PCP), an evolutionarily conserved developmental process originally described in Drosophila melanogaster, is essential to the control of tissue morphogenesis and development of polarized structures in metazoans. Its importance in human diseases is best demonstrated in polycystic kidney disease, hearing loss, Bardet Biedl syndrome, neural tube closure defects and cancer. PCP involves a set of evolutionarily conserved PCP genes encoding WNT ligands, transmembrane (vangl2, frizzled, fat, dachsous) and cytoplasmic (scribble, prickle, dishevelled, diego) molecules triggering a genetically well-defined non-canonical WNT-JNK pathway. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed non-canonical WNT/PCP signaling as a therapeutic target. Here we show that the archetypal non-canonical WNT/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumor 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 in breast cancer cells and in Xenopus. This proliferative signaling 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 signaling is thus a potential target for breast cancer therapy. Puvirajesinghe T.M., et al. Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signaling in breast cancer. Nature Communications, in press. Sebbagh M. and Borg J.-P. Insight into Planar Cell Polarity. (2014) Invited review in Experimental Cell Research, 328:284-295. Belotti E., et al. The human PDZome: a gateway to PDZ mediated functions. (2013) Mol Cell Proteomics, 12: 2587-603. Citation Format: Jean-Paul Borg, Puvirajesinghe Tania, François Bertucci, Daniel Birnbaum, Ashish Jain, Terje Johansen, Pierluigi Scerbo, Laurent Kodjabachian. Identification of p62/SQSTM1 as a component of non-canonical WNT VANGL2-JNK signaling in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4622.