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Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling

Berenjeno, Inma M., Piñeiro, Roberto, Castillo, Sandra D., Pearce, Wayne, McGranahan, Nicholas, Dewhurst, Sally M., Meniel, Valerie, Birkbak, Nicolai J., Lau, Evelyn, Sansregret, Laurent, Morelli, Daniele, Kanu, Nnennaya, Srinivas, Shankar, Graupera, Mariona, Parker, Victoria E. R., Montgomery, Karen G., Moniz, Larissa S., Scudamore, Cheryl L., Phillips, Wayne A., Semple, Robert K., Clarke, Alan, Swanton, Charles and Vanhaesebroeck, Bart 2017. Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling. Nature Communications 8 (1) , 1773. 10.1038/s41467-017-02002-4

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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 Pik3caH1047R 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 PIK3CAH1047R 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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: Nature Publishing Group
ISSN: 2041-1723
Date of First Compliant Deposit: 13 December 2017
Date of Acceptance: 1 November 2017
Last Modified: 14 Dec 2017 12:23
URI: http://orca.cf.ac.uk/id/eprint/107569

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