Breast cancers that have an overactive PI3K enzyme, involved in cell growth and division, tend to be more aggressive and to spread and divide more like stem cells. But a new study by Ralitsa Madsen of University College London and colleagues publishing November 11th in the journal PLOS Genetics uncovers a surprising relationship between PI3K activity and mutations in the PIK3CA gene that codes for the enzyme. Breast cancer tumors with one mutant copy of the PIK3CA gene tend to have lower PI3K activity. In comparison, patients with two or more copies often had higher PI3Kα activity, resulting in more aggressive tumors and a poorer prognosis for patients with certain types of breast cancer.
Experiments in the lab previously showed that two but not one mutant PIK3CA gene can promote a persistent stem cell state—a quality called "stemness". But until now, there was no evidence from human patients to support this idea. In the new study, researchers investigate the relationship among PI3K mutations, PI3K activity and stemness in breast cancer. They used publicly available data from nearly 3,000 breast cancer tumors and applied computational methods to infer PI3K activity and stemness. They discovered that aggressive tumors had more PI3K activity and a higher degree of stemness. However, they were surprised to find that cancer cells with only one mutant copy of PIK3CA had lower levels of stemness and are potentially less aggressive.
The new study supports the idea that overactive PI3K enzymes are linked to more aggressive breast cancers. Additionally, the researchers warn that the number of copies of mutant PIK3CA mutations in a tumor may affect how it responds to cancer therapies. They conclude that this information, along with data on PI3K activity, should be considered when choosing patients to participate in clinical trials of new drugs.
Madsen adds, “Breast cancer stratification by PIK3CA mutant dose reveals a counterintuitive relationship with functional indices of PI3K pathway activity and tumor dedifferentiation.”
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Citation: Madsen RR, Erickson EC, Rueda OM, Robin X, Caldas C, Toker A, et al. (2021) Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. PLoS Genet 17(11): e1009876. https://doi.org/10.1371/journal.pgen.1009876
Author Countries: United Kingdom, United States, Switzerland
Funding: R.R.M. is supported by a Sir Henry Wellcome Fellowship (220464/Z/20/Z). R.K.S. is supported by the Wellcome Trust (210752/Z/18/Z). Work in the laboratory of B.V. is supported by Cancer Research UK (C23338, A25722) and PTEN Research. O.M.R. and C.C. are supported by Cancer Research UK. This work was supported by grants from the NCI (R35 CA253097 to A.T. and F31CA254000 to E.C.E.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Method of Research
Subject of Research
Lab-produced tissue samples
I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.K.S. consults for Novartis (Cambridge, MA, USA) on use of PI3K inhibitors in overgrowth syndromes and has consulted for HotSpot Therapeutics (Boston, MA, USA); B.V. is a consultant for iOnctura (Geneva, Switzerland), Venthera (Palo Alto, CA, USA), Olema Pharmaceuticals (San Francisco, US) and Pharming (Leiden, The Netherlands).