Editors' ChoiceCancer

Inducing tumor heterogeneity with PI3K

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Sci. Signal.  08 Sep 2015:
Vol. 8, Issue 393, pp. ec253
DOI: 10.1126/scisignal.aad3711

Breast cancers are typically heterogeneous, meaning that the tumors contain cells of different types with apparently different lineages. Koren et al. and Brohée et al. showed that expression of PIK3CAH1047R, a cancer-associated mutant version of the catalytic subunit of phosphatidylinositol 3-kinase, in lineage-restricted (basal or luminal mammary epithelial) cells produced mammary tumors in mice that contained cells with properties of basal cells, luminal cells, and cells with properties of both. Each group selectively expressed PIK3CAH1047R in either basal cells or luminal cells in mouse mammary tissue and examined the properties of the resulting tumors using lineage-tracing experiments, marker analysis, and transcriptional profiling. When mutant PIK3CA was introduced into mouse mammary basal epithelial cells, the tumors developed more slowly than when it was introduced into luminal cells and had a less aggressive phenotype, which was confirmed in various ex vivo or cell culture experiments. Analysis of the markers for basal or luminal cell types in the tumors derived from PIK3CAH1047R expressed initially in cells of either lineage showed that some cells had markers of both luminal and basal cells, some had markers similar to that of the initiating cell, and some had markers similar to that of the other type, suggesting that PIK3CAH1047R induces basal and luminal cells to undergo dedifferentiation to a multipotent state from which cells of either basal or luminal type can be produced. Thus, analyzing human tumors for the type of cell in breast cancer may not be an indication of the cell of tumor origin. Microarray analysis, analysis of time to tumor development, and analysis of tumor type indicated that when PIK3CAH1047R occurred initially in a luminal cell, more aggressive cancers resulted. This pair of studies provides three key messages: Specific PI3K mutants induce multipotency in breast epithelial cells, the tumor-initiating cell in which the mutant occurs (luminal or basal) dictates the severity of disease, and that analysis of tumor cells for basal or luminal markers may not be an indication of the cell of origin.

S. Koren, L. Reavie, J. P. Couto, D. De Silva, M. B. Stadler, T. Roloff, A. Britschgi, T. Eichlisberger, H. Kohler, O. Aina, R. D. Cardiff, M. Bentires-Alj, PIK3CAH1047R induces multipotency and multi-lineage mammary tumours. Nature. 525, 114–118 (2015). [PubMed]

A. Van Keymeulen, M. Y. Lee, M. Ousset, S. Brohée, S. Rorive, R. R. Giraddi, A. Wuidart, G. Bouvencourt, C. Dubois, I. Salmon, C. Sotiriou, W. A. Phillips, C. Blanpain, Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature 525, 119–123 (2015). [PubMed]