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Nat Commun. 2017 Nov 24;8(1):1773. doi: 10.1038/s41467-017-02002-4.

Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.

Author information

1
UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London, London, WC1E 6DD, UK. i.berenjeno@ucl.ac.uk.
2
UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London, London, WC1E 6DD, UK.
3
Roche-Chus Joint Unit, Complexo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana S/N, 15706, Santiago de Compostela, Spain.
4
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals, 72 Huntley Street, London, WC1E 6DD, UK.
5
European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, CF24 4HQ, UK.
6
Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 2JD, UK.
7
Vascular Signalling Laboratory, Institut d´Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, 08908, Spain.
8
Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
9
Cancer Biology and Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia.
10
Mary Lyon Centre, MRC Harwell, Harwell, OX11 0RD, UK.
11
UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London, London, WC1E 6DD, UK. charles.swanton@crick.ac.uk.
12
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UCL Cancer Institute and Hospitals, 72 Huntley Street, London, WC1E 6DD, UK. charles.swanton@crick.ac.uk.
13
UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London, London, WC1E 6DD, UK. bart.vanh@ucl.ac.uk.

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.

PMID:
29170395
PMCID:
PMC5701070
DOI:
10.1038/s41467-017-02002-4
[Indexed for MEDLINE]
Free PMC Article

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