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.
Highlights
The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development
We identify p62/sequestosome-1 as a novel VANGL2-binding partner in breast cancer cells. p62/SQSTM1 is an intracellular Phox and Bem1p (PB1) domain-containing scaffold protein involved in important processes such as selective autophagy, cell signalling and induction of epithelial–mesenchymal transition (EMT)14,15. p62/SQSTM1 has been linked to several diseases such as Paget’s disease of bone, neurodegenerative diseases, liver disorders and cancer[16]
The analysis of available array-comparative genomic hybridization data from 208 samples revealed that half of them show a gain of VANGL2 DNA copy number, which is statistically correlated with mRNA upregulation (Student’s t-test, Po0.001; Fig. 1b)
Summary
The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. 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. This proliferative pathway is upregulated in breast cancer patients with shorter survival and in patientderived xenografts (PDXs), and is sensitive to inhibition of JNK and of the VANGL2–p62/SQSTM1 interaction These data describe a non-canonical Wnt/PCP pathway overexpressing VANGL2 in aggressive breast cancer and identify p62/SQSTM1 as an important player in VANGL2–JNK signalling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
