4.6 Article

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

Journal

PLOS GENETICS
Volume 17, Issue 11, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1009876

Keywords

-

Funding

  1. Sir Henry Wellcome Fellowship [220464/Z/20/Z]
  2. Wellcome Trust [210752/Z/18/Z]
  3. Cancer Research UK [C23338, A25722]
  4. PTEN Research
  5. NCI [R35 CA253097, F31CA254000]
  6. Wellcome Trust [220464/Z/20/Z] Funding Source: Wellcome Trust

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This study shows a correlation between PI3K/AKT/mTOR signaling and stemness in human breast cancer, with different associations based on PIK3CA genotype. The findings support the potential benefit of patient stratification based on a combination of genetic information and transcriptomic indices related to PI3K signaling activation.
A PI3K alpha-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110 alpha. 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 PIK3CA(H1047R) 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.

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