Show simple item record

dc.contributor.authorAbdel-Fatah, TM
dc.contributor.authorPowe, DG
dc.contributor.authorAgboola, J
dc.contributor.authorAdamowicz-Brice, M
dc.contributor.authorBlamey, RW
dc.contributor.authorLopez-Garcia, MA
dc.contributor.authorGreen, AR
dc.contributor.authorReis-Filho, JS
dc.contributor.authorEllis, IO
dc.date.accessioned2018-08-24T11:09:32Z
dc.date.issued2010-03
dc.identifier.citationThe Journal of pathology, 2010, 220 (4), pp. 419 - 434
dc.identifier.issn0022-3417
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2384
dc.identifier.eissn1096-9896
dc.identifier.doi10.1002/path.2663
dc.description.abstractWe hypothesized that the functional status of p53 transcriptional pathways, rather than p53 protein expression alone, could accurately discriminate between low- and high-risk breast carcinoma (BC) and inform about individuals' tumour biological behaviour. To test this, we studied a well-characterized series of 990 BCs with long-term follow-up, immunohistochemically profiled for p53, its main regulators and downstream genes. Results were validated in an independent series of patients (n = 245) uniformly treated with adjuvant anthracycline-based chemotherapy. Eleven p53 transcriptional phenotypes were identified with just two main clinical outcomes. (a) Low risk/good prognosis group (active/partially inactive p53 pathways), defined as p53(+/-)/MDM4(+)/MDM2(+/-)/Bcl2(+/-)/p21(+/-), p53(-)/MDM4(-)/MDM2(+)/Bcl2(+)/p21(+/-) and p53(+/-)/MDM4(-)/MMD2(-)/Bcl2(+)/p21(+/-). These tumours had favourable clinicopathological characteristics, including ER(+) and long survival after systemic adjuvant-therapy (AT). (b) High risk/poor prognosis group (completely inactive p53 pathways), defined as p53(+/-)/MDM4(-) MDM2(-)/Bcl2(-)/p21(-), p53(-)/MDM4(-) MDM2(+)/Bcl2(-)/p21(-) and p53(+/-)/MDM4(-)/MDM2(-)/Bcl2(-)/p21(+). These tumours were characterized by aggressive clinicopathological characteristics and showed shortened survival when treated with AT. Completely inactive p53 pathways but intact p21 axis p53(+/-)/MDM4(-)/MDM2(-)/Bcl2(-)/p21(+) had the worst prognosis, particularly patients who received AT. Multivariate Cox regression models, including validated prognostic factors for both test and validation series, revealed that the functional status of p53 transcriptional pathways was an independent prognosticator for BC-specific survival (HR 2.64 and 4.5, p < 0.001, respectively) and disease-free survival (HR 1.93 and 2.5, p < 0.001, respectively). In conclusion, p53 functional status determined by assessment of p53 regulatory and downstream targets provides independent prognostic value and may help determine more adequate therapeutic regimens for specific subgroups of breast cancer patients.
dc.formatPrint
dc.format.extent419 - 434
dc.languageeng
dc.language.isoeng
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectCell Cycle Proteins
dc.subjectNeoplasm Proteins
dc.subjectProto-Oncogene Proteins
dc.subjectProto-Oncogene Proteins c-bcl-2
dc.subjectNuclear Proteins
dc.subjectPrognosis
dc.subjectTreatment Outcome
dc.subjectChemotherapy, Adjuvant
dc.subjectSurvival Analysis
dc.subjectFollow-Up Studies
dc.subjectTranscription, Genetic
dc.subjectFemale
dc.subjectTumor Suppressor Protein p53
dc.subjectProto-Oncogene Proteins c-mdm2
dc.subjectBiomarkers, Tumor
dc.titleThe biological, clinical and prognostic implications of p53 transcriptional pathways in breast cancers.
dc.typeJournal Article
rioxxterms.versionofrecord10.1002/path.2663
rioxxterms.licenseref.startdate2010-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of pathology
pubs.issue4
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Molecular Pathology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Molecular Pathology
pubs.publication-statusPublished
pubs.volume220
pubs.embargo.termsNot known
icr.researchteamMolecular Pathologyen_US
dc.contributor.icrauthorReis-Filho, Jorge Sergioen


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following collection(s)

Show simple item record