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PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers

Cell Death & Differentiation (2018) | Download Citation

Abstract

PARP3 has been shown to be a key driver of TGFβ-induced epithelial-to-mesenchymal transition (EMT) and stemness in breast cancer cells, emerging as an attractive therapeutic target. Nevertheless, the therapeutic value of PARP3 inhibition has not yet been assessed. Here we investigated the impact of the absence of PARP3 or its inhibition on the tumorigenicity of BRCA1-proficient versus BRCA1-deficient breast cancer cell lines, focusing on the triple-negative breast cancer subtype (TNBC). We show that PARP3 knockdown exacerbates centrosome amplification and genome instability and reduces survival of BRCA1-deficient TNBC cells. Furthermore, we engineered PARP3−/− BRCA1-deficient or BRCA1-proficient TNBC cell lines using the CRISPR/nCas9D10A gene editing technology and demonstrate that the absence of PARP3 selectively suppresses the growth, survival and in vivo tumorigenicity of BRCA1-deficient TNBC cells, mechanistically via effects associated with an altered Rictor/mTORC2 signaling complex resulting from enhanced ubiquitination of Rictor. Accordingly, PARP3 interacts with and ADP-ribosylates GSK3β, a positive regulator of Rictor ubiquitination and degradation. Importantly, these phenotypes were rescued by re-expression of a wild-type PARP3 but not by a catalytic mutant, demonstrating the importance of PARP3’s catalytic activity. Accordingly, reduced survival and compromised Rictor/mTORC2 signaling were also observed using a cell-permeable PARP3-specific inhibitor. We conclude that PARP3 and BRCA1 are synthetic lethal and that targeting PARP3’s catalytic activity is a promising therapeutic strategy for BRCA1-associated cancers via the Rictor/mTORC2 signaling pathway.

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Acknowledgements

This work was supported by the Association pour la Recherche contre le Cancer, Ligue Nationale Contre le Cancer, CNRS, Université de Strasbourg and Ramon Areces Foundation. This work has been published within the LABEX ANR-10-LABX-0034_Medalis.

Author information

Author notes

  1. These authors contributed equally: Carole Beck, José Manuel Rodriguez-Vargas

  2. Edited by: J.P. Medema

Affiliations

  1. Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d’Excellence Medalis, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l’Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412, Illkirch, France

    • Carole Beck
    • , José Manuel Rodriguez-Vargas
    • , Christian Boehler
    • , Najat Hanini
    • , Valérie Schreiber
    •  & Françoise Dantzer
  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France

    • Isabelle Robert
    • , Vincent Heyer
    •  & Bernardo Reina San Martin
  3. Institut National de la Santé et de la Recherche Médicale (INSERM), U964, Illkirch, France

    • Isabelle Robert
    • , Vincent Heyer
    •  & Bernardo Reina San Martin
  4. Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France

    • Isabelle Robert
    • , Vincent Heyer
    •  & Bernardo Reina San Martin
  5. Université de Strasbourg, Illkirch, France

    • Isabelle Robert
    • , Vincent Heyer
    •  & Bernardo Reina San Martin
  6. Laboratoire de radiopathologie, CEA-DRF/INSERM U967, Institut de biologie François Jacob, Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), 18 route du Panorama, 92265, Fontenay-aux-Roses, France

    • Laurent R. Gauthier
  7. EMT and Cancer Cell Plasticity, Centre de Recherche en Cancérologie, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, F-69008, France

    • Agnès Tissier
  8. Department of chemistry, Umea University, Umea, Sweden

    • Mikael Elofsson

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Françoise Dantzer.

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DOI

https://doi.org/10.1038/s41418-018-0233-1