Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity

Abstract

Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. 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 Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice 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 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 Pik3ca(H1047R) 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 Pik3ca(H1047R) 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 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.

Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay

“…Hi basal cell 1,000 21 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Intriguingly, human basal-and luminal-derived tumors demonstrate histologically distinct phenotypes when challenged with the same oncogenes, MYC and AKT1. Tumors derived from basal cells are of a higher grade than tumors derived from luminal cells.…”

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

“…7 Further studies will determine whether the potential MYC-induced cell fate switch observed here bears similarities to recent discoveries of oncogene-induced cell fate conversions in lineage restricted subpopulations and whether it contributes to tumor heterogeneity in human breast cancer. 47,48 …”

Sox2 is dispensable for primary melanoma and metastasis formation

“…However, we suggest that the pathophysiological role of Sox2 in melanoma can best be assessed in genetically engineered mouse melanoma models, in which melanoma spontaneously develops within an undisturbed stromal environment and without prior tumor cell isolation which might influence the cells' behavior. Importantly, Cancer formation has been associated with reactivation of embryonic or organ-specific stem cell programs 40,41 . Accordingly, Sox2 has been functionally implicated in several tumors emerging from tissues harboring Sox2-positive stem cells 1,31 .…”