Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.
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 aggr...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-11-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009876&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849470000363995136 |
|---|---|
| author | Ralitsa R Madsen Emily C Erickson Oscar M Rueda Xavier Robin Carlos Caldas Alex Toker Robert K Semple Bart Vanhaesebroeck |
| author_facet | Ralitsa R Madsen Emily C Erickson Oscar M Rueda Xavier Robin Carlos Caldas Alex Toker Robert K Semple Bart Vanhaesebroeck |
| author_sort | Ralitsa R Madsen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3d2b6e7a73c244b6bd885448cf033e57 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2021-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-3d2b6e7a73c244b6bd885448cf033e572025-08-20T03:25:16ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042021-11-011711e100987610.1371/journal.pgen.1009876Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.Ralitsa R MadsenEmily C EricksonOscar M RuedaXavier RobinCarlos CaldasAlex TokerRobert K SempleBart VanhaesebroeckA 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009876&type=printable |
| spellingShingle | Ralitsa R Madsen Emily C Erickson Oscar M Rueda Xavier Robin Carlos Caldas Alex Toker Robert K Semple Bart Vanhaesebroeck Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. PLoS Genetics |
| title | Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. |
| title_full | Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. |
| title_fullStr | Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. |
| title_full_unstemmed | Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. |
| title_short | Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype. |
| title_sort | positive correlation between transcriptomic stemness and pi3k akt mtor signaling scores in breast cancer and a counterintuitive relationship with pik3ca genotype |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009876&type=printable |
| work_keys_str_mv | AT ralitsarmadsen positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype AT emilycerickson positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype AT oscarmrueda positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype AT xavierrobin positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype AT carloscaldas positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype AT alextoker positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype AT robertksemple positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype AT bartvanhaesebroeck positivecorrelationbetweentranscriptomicstemnessandpi3kaktmtorsignalingscoresinbreastcancerandacounterintuitiverelationshipwithpik3cagenotype |