Mammary gland tumor.



August 12, 2015

Common breast cancer mutation induces multipotency and tumor heterogeneity

Understanding how different cell populations arise within a tumor – so-called tumor heterogeneity – is widely regarded as a major challenge for cancer biology. Mohamed Bentires-Alj and his group at the FMI have discovered how the most frequent mutation in human breast cancer leads to tumor heterogeneity. The PI3-kinase mutation forces cells back into a dedifferentiated, stem-like state from which tumors containing cells of various lineages can develop. These results have been published in Nature.

Breast cancer is not simply breast cancer – as has been known for some time, tumors grow and develop differently in different patients. This diversity has prompted the development of more individualized therapeutic approaches, which have already shown great promise. Recently, however, scientists discovered that a single tumor is composed of a variety of cell types, with different mutations and developmental potentials. Some of these cell types vary subtly, others substantially, some are frequent, others less so, and they respond differently to therapy. Most importantly, these differences between cells from the same patient have important consequences for how cancer is diagnosed and treated. However, it has remained unclear how tumor heterogeneity arises.

In a study published in Nature, Mohamed Bentires-Alj and his group have now shown how a common breast cancer mutation can lead to tumor heterogeneity.

“Heterogeneity is one of the most important and clinically relevant areas of development, stem cell and cancer research,” says Bentires-Alj. “In The Origin of Species, Darwin already discussed an experiment showing that diversity can make communities more productive. This suggests how tumor heterogeneity can affect prognosis, response to therapy and metastasis. Factors that enhance cancer cell fitness are clearly detrimental for patients.”

One of the most frequent genetic alterations occurring in human breast cancer is activation of the PI3-kinase pathway. This signaling pathway is activated in approximately 70% of breast cancers. In 20–40% of cases, activation is due to a mutation in one of the subunits of the PI3 kinase – PIK3CAH1047R.

In the study, PhD student Shany Koren, together with colleagues in Bentires-Alj’s group, used in situ genetic lineage tracing to unravel the potential of PIK3CAH1047R to induce tumor heterogeneity. Koren explains: “We observed that the mutation forced cells that were already committed to form a particular layer of the mammary gland back into a more stem-like state. These dedifferentiated cells then gave rise to a variety of different cell lineages, thus inducing the formation of multi-lineage tumors.”

Even though these tumors initially all bore the same mutation, after dedifferentiation the cell fates varied substantially, and the tumors formed were heterogeneous – also with respect to prognosis.

Bentires-Alj comments: “This is a first indication of how intra-tumor heterogeneity can arise in PIK3CA mutant cells. While we were able to trace the first steps towards heterogeneous, multi-lineage tumors, we now need even more sophisticated tools to characterize these cells during tumor development. What determines the different outcomes? What are the roles of secondary mutations, and what about the interplay with the environment? Only with this knowledge can we hope to improve our methods of diagnosis and treatment.”

Original publication
Koren S, Reavie L, Pinto do Couto J, De Silva D, Stadler MB, Roloff T, Britschgi A, Eichlisberger T, Kohler H, Aina O, Cardiff RD, Bentires-Alj M* (2015) PIK3CAH1047R induces multipotency and multi-lineage mammary tumours. Nature doi:10.1038/nature14669

Dr. Mohamed Bentires-Alj,, Tel. +41 61 697 40 48
The Bentires-Alj lab investigates fundamental molecular mechanisms controlling normal and neoplastic breast cell fate, metastasis and resistance to targeted therapy.
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