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Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.

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.

SUBMITTER: Berenjeno IM

PROVIDER: S-EPMC5701070 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.

Berenjeno Inma M IM Piñeiro Roberto R Castillo Sandra D SD Pearce Wayne W McGranahan Nicholas N Dewhurst Sally M SM Meniel Valerie V Birkbak Nicolai J NJ Lau Evelyn E Sansregret Laurent L Morelli Daniele D Kanu Nnennaya N Srinivas Shankar S Graupera Mariona M Parker Victoria E R VER Montgomery Karen G KG Moniz Larissa S LS Scudamore Cheryl L CL Phillips Wayne A WA Semple Robert K RK Clarke Alan A Swanton Charles C Vanhaesebroeck Bart B

Nature communications 20171124 1

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, a ...[more]

PMID: 29170395

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Project description:Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1-3. Pik3ca and p53 are the two most frequently mutated genes and are associated with different types of human breast cancers4. The cellular origin and the mechanisms leading to Pik3ca-induced tumour heterogeneity remain unknown. Here, we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and its impact on tumour heterogeneity. Surprisingly, oncogenic Pik3ca-H1047R expression at physiological levels5 in basal cells (BCs) using K5CREERT2 induced the formation of luminal ER+PR+ tumours, while its expression in luminal cells (LCs) using K8CREERT2 gave rise to luminal ER+PR+ tumours or basal-like ER-PR- tumours. Concomitant deletion of p53 and expression of Pik3ca-H1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca-H1047R in unipotent BCs gave rise to luminal-like cells, while its expression in unipotent LCs gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that have undergone cell fate transition upon Pik3ca-H1047R expression in unipotent progenitors demonstrate a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures, characteristic of the different cell fate switches that occur upon Pik3ca-H1047R expression in BC and LCs, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca-H1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation. Luminal and basal cells, or tumour cells, from mice in which expression of PIK3CA-H1047R and YFP (and in some conditions loss of p53) was targeted in basal cells using K5CREERT2 or in luminal cells using K8CREERT2 were FACS isolated and RNA was extracted before being hybridized Affymetrix microarrays.

Dataset Information

Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.

Publications

Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.

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