IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_s41467-017-02002-4.html
   My bibliography  Save this article

Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling

Author

Listed:
  • Inma M. Berenjeno

    (University College London)

  • Roberto Piñeiro

    (University College London
    Complexo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana S/N)

  • Sandra D. Castillo

    (University College London)

  • Wayne Pearce

    (University College London)

  • Nicholas McGranahan

    (The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals)

  • Sally M. Dewhurst

    (The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals)

  • Valerie Meniel

    (Cardiff University)

  • Nicolai J. Birkbak

    (The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals)

  • Evelyn Lau

    (University College London)

  • Laurent Sansregret

    (University College London
    The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals)

  • Daniele Morelli

    (University College London)

  • Nnennaya Kanu

    (The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals)

  • Shankar Srinivas

    (University of Oxford)

  • Mariona Graupera

    (Institut d´Investigació Biomèdica de Bellvitge (IDIBELL))

  • Victoria E. R. Parker

    (University of Cambridge, Addenbrooke’s Hospital)

  • Karen G. Montgomery

    (Peter MacCallum Cancer Centre)

  • Larissa S. Moniz

    (University College London)

  • Cheryl L. Scudamore

    (Mary Lyon Centre, MRC Harwell)

  • Wayne A. Phillips

    (Peter MacCallum Cancer Centre)

  • Robert K. Semple

    (University of Cambridge, Addenbrooke’s Hospital)

  • Alan Clarke

    (Cardiff University)

  • Charles Swanton

    (University College London
    The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals)

  • Bart Vanhaesebroeck

    (University College London)

Abstract

Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.

Suggested Citation

  • Inma M. Berenjeno & Roberto Piñeiro & Sandra D. Castillo & Wayne Pearce & Nicholas McGranahan & Sally M. Dewhurst & Valerie Meniel & Nicolai J. Birkbak & Evelyn Lau & Laurent Sansregret & Daniele More, 2017. "Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02002-4
    DOI: 10.1038/s41467-017-02002-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-017-02002-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-017-02002-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02002-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.