Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling

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 Morelli, Nnennaya Kanu, Shankar Srinivas, Mariona Graupera, Victoria E. R. Parker, Karen G. Montgomery, Larissa S. Moniz, Cheryl L. Scudamore, Wayne A. Phillips, Robert K. Semple, Alan Clarke, Charles Swanton () and Bart Vanhaesebroeck ()
Additional contact information
Inma M. Berenjeno: University College London
Roberto Piñeiro: University College London
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
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
Bart Vanhaesebroeck: University College London

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02002-4

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