Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29170395.
- Also identified by DOI 10.1038/s41467-017-02002-4 and PMC identifier 5701070.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <sup>H1047R</sup> 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 <sup>H1047R</sup> 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.
Medical subject headings
- Breast Neoplasms
- Centrosome
- Class I Phosphatidylinositol 3-Kinases
- Gene Amplification
- Genome
- Phosphatidylinositol 3-Kinases