Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer

Nat Commun. 2016 Jan 12:7:10318. doi: 10.1038/ncomms10318.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / genetics*
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Lobular / genetics*
  • Carcinoma, Lobular / metabolism
  • Carcinoma, Lobular / pathology
  • Cell Line, Tumor
  • Cell Migration Assays
  • Cell Movement / genetics
  • Cell Polarity
  • Cell Proliferation / genetics
  • DNA Copy Number Variations
  • Embryo, Nonmammalian
  • Female
  • Humans
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Signaling System / genetics*
  • Mass Spectrometry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Microscopy, Electron
  • Middle Aged
  • Neoplasm Transplantation
  • Prognosis
  • Proportional Hazards Models
  • RNA, Messenger / metabolism*
  • Sequestosome-1 Protein
  • Wnt Signaling Pathway / genetics*
  • Xenopus

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RNA, Messenger
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • VANGL2 protein, human