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

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Puvirajesinghe, Tania M. | Bertucci, François | Jain, Ashish | Scerbo, Pierluigi | Belotti, Edwige | Audebert, Stéphane | Sebbagh, Michael | Lopez, Marc | Brech, Andreas | Finetti, Pascal | Charafe-Jauffret, Emmanuelle | Chaffanet, Max | Castellano, Rémy | Restouin, Audrey | Marchetto, Sylvie | Collette, Yves | Gonçalvès, Anthony | Macara, Ian | Birnbaum, Daniel | Kodjabachian, Laurent | Johansen, Terje | Borg, Jean-Paul

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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