Journal article
Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling
IM Berenjeno, R Piñeiro, SD Castillo, W Pearce, N McGranahan, SM Dewhurst, V Meniel, NJ Birkbak, E Lau, L Sansregret, D Morelli, N Kanu, S Srinivas, M Graupera, VER Parker, KG Montgomery, LS Moniz, CL Scudamore, WA Phillips, RK Semple Show all
Nature Communications | Published : 2017
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 prev..
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Awarded by University College London Hospitals Biomedical Research Centre
Funding Acknowledgements
We thank Susana Godinho for feedback and experimental advice, Maria Whitehead for assistance in the writing of the manuscript, Romain Galmes and Elena Lopez-Guadamillas for experimental help, members of the Cell Signalling Group for critically reading the manuscript and Susan M. Dymecki for the Flpe-ER<SUP>T2</SUP> mice. We are grateful to the human subjects who provided primary cells for this study. Personal fellowships were from EU Marie Curie (PIEF-GA-2008-219945; to IMB), EMBO (ALTF 165-2013; to S.C.) and the Ong Hin Tiang & Ong Sek Pek Foundation, Malaysia (to E.L.). M.G. was supported by the Ministry of Economy and Innovation (Spain) (SAF2014-59950-P), the Catalan Government (2014-SGR-725), the People Programme (Marie Curie Actions) from the European Union's Seventh Framework Programme FP7/2007-2013 (REA grant agreement 317250), the Institute of Health Carlos III and the European Regional Development Fund under the integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE). W.A.P. was supported by the National Health and Medical Research Council (NHMRC) of Australia (project grant No. 1080491). V.E.R.P. was supported by the Wellcome Trust (097721/Z/11/Z). R.K.S. is supported by the Wellcome Trust (WT098498), the Medical Research Council (MRC_MC_UU_12012/5). V.M. and A.C. were supported by Cancer Research UK (C1295/A15937). S.S is supported by BBSRC (BB/J00989X/1) and Wellcome Trust Senior Investigator Award (103788/Z/14/Z). C.S. is a senior Cancer Research UK clinical research fellow and is funded by Cancer Research UK (TRACERx), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council (THESEUS) and National Institute for Health Research University College London Hospitals Biomedical Research Centre. B.V. is supported by Cancer Research UK (C23338/A15965) and the UK NIHR University College London Hospitals Biomedical Research Centre.