Details

Autor(en) / Beteiligte

• Van Keymeulen, Alexandra
• Lee, May Yin
• Ousset, Marielle
• Brohée, Sylvain
• Rorive, Sandrine
• Giraddi, Rajshekhar R.
• Wuidart, Aline
• Bouvencourt, Gaëlle
• Dubois, Christine
• Salmon, Isabelle
• Sotiriou, Christos
• Phillips, Wayne A.
• Blanpain, Cédric

Titel

Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity

Ist Teil von

• Nature (London), 2015-09, Vol.525 (7567), p.119-123

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• PIK3CA mutations are associated with distinct types of human breast cancers but the cellular origin and mechanisms responsible for this heterogeneity were unclear; here, using a genetic approach in mice, PIK3CA mutations are shown to activate a genetic program directing multiple cell fates in normally lineage-restricted cell types. Effects of mutant PIK3CA on mammary cell fate PIK3CA mutations are associated with distinct types of human breast cancers, however, the cellular origin and the mechanisms responsible for this heterogeneity was unclear. Two groups reporting in this issue of Nature have used a genetic approach in mice to demonstrate that tumours originating from different breast cell types induced cancer with different morphologies, growth and invasiveness properties. PIK3CA mutations appear to activate a genetic program directing multiple cells fates in normally lineage-restricted cell types. 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 1 , 2 . PIK3CA and P53 (also known as TP53 ) are the two most frequently mutated genes and are associated with different types of human breast cancers 3 . 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 4 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.