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dc.contributor.authorMadsen, Ralitsa R
dc.contributor.authorErickson, Emily C
dc.contributor.authorRueda Palacio, Oscar
dc.contributor.authorRobin, Xavier
dc.contributor.authorCaldas, Carlos
dc.contributor.authorToker, Alex
dc.contributor.authorSemple, Robert K
dc.contributor.authorVanhaesebroeck, Bart
dc.date.accessioned2022-01-07T11:12:03Z
dc.date.available2022-01-07T11:12:03Z
dc.date.issued2021-11
dc.identifier.issn1553-7390
dc.identifier.otherPMC8584750
dc.identifier.other34762647
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332293
dc.descriptionFunder: pten research foundation
dc.description.abstractA 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.
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1553-7404
dc.sourcenlmid: 101239074
dc.titlePositive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.
dc.typeArticle
dc.date.updated2022-01-07T11:12:02Z
prism.issueIdentifier11
prism.publicationNamePLoS Genet
prism.volume17
dc.identifier.doi10.17863/CAM.79740
dcterms.dateAccepted2021-10-13
rioxxterms.versionofrecord10.1371/journal.pgen.1009876
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidMadsen, Ralitsa R [0000-0001-8844-5167]
dc.contributor.orcidErickson, Emily C [0000-0003-3494-2605]
dc.contributor.orcidRueda Palacio, Oscar [0000-0003-0008-4884]
dc.contributor.orcidRobin, Xavier [0000-0002-6813-3200]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.contributor.orcidToker, Alex [0000-0003-0723-4419]
dc.contributor.orcidSemple, Robert K [0000-0001-6539-3069]
dc.contributor.orcidVanhaesebroeck, Bart [0000-0002-7074-3673]
dc.identifier.eissn1553-7404
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (60098573)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (CB4140)
pubs.funder-project-idCancer Research UK (A3086)
pubs.funder-project-idCancer Research UK (A9401)
pubs.funder-project-idCancer Research UK (A16942)
pubs.funder-project-idCancer Research UK (A7325)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (unknown)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
pubs.funder-project-idCancer Research UK (A7199)
pubs.funder-project-idCancer Research UK (A15580)
cam.issuedOnline2021-11-11


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International