Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1,2. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers3. 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 the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3caH1047R mutant expression at physiological levels4 in basal cells using keratin (K)5-CreERT2 mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReERT2 mice gave rise to luminal ER+PR+ tumours or basal-like ER−PR− tumours. Concomitant deletion of p53 and expression of Pik3caH1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3caH1047R in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3caH1047R expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3caH1047R expression in basal and luminal cells, 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 Pik3caH1047R 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.
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Gene Expression Omnibus
Microarrays have been deposited in the Gene Expression Omnibus under accession number GSE69290.
C.B. is an investigator of WELBIO, A.V.K. is Chercheur Qualifié of the FNRS, C.S. is Maître de Recherche of the FNRS, M.Y.L. is supported by the Agency for Science, Technology and Research (A*STAR, Singapore) fellowship, M.O. and A.W. are supported by FNRS fellowships, R.R.G. is supported by a TELEVIE fellowship and S.B. is supported by the foundation “Amis de l’institut Jules Bordet”. The Center for Microscopy and Molecular Imaging is supported by the European Regional Development Fund and Wallonia. W.A.P. is supported by project grants from the National Health and Medical Research Council of Australia. This work was supported by the FNRS, TELEVIE, a research grant from the Fondation Contre le Cancer, the ULB fondation, the Fond Yvonne Boël, the Fond Gaston Ithier, the foundation Bettencourt Schueller, the foundation Baillet Latour, and the European Research Council.