Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.

Autor: Madsen RR; University College London Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom., Erickson EC; Department of Pathology, Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America., Rueda OM; Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom.; NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom., Robin X; SIB Swiss Institute of Bioinformatics, Biozentrum, University of Basel, Basel, Switzerland., Caldas C; Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom.; NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom., Toker A; Department of Pathology, Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America., Semple RK; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Vanhaesebroeck B; University College London Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2021 Nov 11; Vol. 17 (11), pp. e1009876. Date of Electronic Publication: 2021 Nov 11 (Print Publication: 2021).
DOI: 10.1371/journal.pgen.1009876
Abstrakt: A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a "biphasic" relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation.
Competing Interests: 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).
Databáze: MEDLINE
Externí odkaz: