PIK3CA^H1047R-Mediated Multipotency Underlies Breast Tumor Heterogeneity

Breast cancer is a heterogeneous disease that can be classified into different subtypes including luminal and basal-like cancers. Oncogenic mutations in the PIK3CA gene are frequently observed in breast cancer and have been shown to promote tumor heterogeneity in mice. However, the mechanisms underlying mutant PIK3CA–driven heterogeneity and the contribution of cell of origin remain unknown. Using genetically engineered mouse models, Van Keymeulen, Lee, and colleagues showed that expression of oncogenic PIK3CA^H1047R in basal cells led to luminal adenomyoepithelial tumor formation, whereas PIK3CA^H1047R expression in luminal cells led to more aggressive and heterogeneous luminal and basal-like tumors. In vivo lineage-tracing experiments revealed that expression of PIK3CA^H1047R in lineage-committed luminal or basal cells gave rise to multipotent clones, suggesting that oncogenic PIK3CA promotes lineage plasticity that induces cellular heterogeneity. Gene expression profiling revealed dynamic regulation of specific transcriptional programs according to the cellular origin, which correlated with tumor subtype and clinical outcome in patients. In line with these results, Koren and colleagues found that forced expression of PIK3CA^H1047R in lineage-restricted murine luminal or basal cells led to dedifferentiation and the expansion of multipotent stem-like cells that co-expressed basal and luminal lineage markers. Moreover, PIK3CA^H1047R-expressing basal cell–driven and luminal cell–driven tumors were characterized by markers of both lineages. PIK3CA^H1047R luminal cell–driven tumors were more aggressive and correlated with malignant human basal-like, HER2⁺, and luminal-B tumors, whereas PIK3CA^H1047R basal cell–driven tumors were highly heterogeneous but mostly benign, indicating that the cell of origin determines tumor heterogeneity and aggressiveness. Together, these data provide evidence that oncogenic PIK3CA drives a multipotent gene transcription program in lineage-committed mammary cells early in tumorigenesis that contributes to intratumor heterogeneity and malignant progression.

Van Keymeulen A, Lee MY, Ousset M, Brohée S, Rorive S, Giraddi RR, et al. Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature 2015;525:119–23.

Koren S, Reavie L, do Couto JP, De Silva D, Stadler MB, Roloff T, et al. PIK3CA^H1047R induces multipotency and multi-lineage mammary tumours. Nature 2015;525:114–8.

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