RGD Reference Report - The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. - Rat Genome Database

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The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers.

Authors: Leong, CO  Vidnovic, N  DeYoung, MP  Sgroi, D  Ellisen, LW 
Citation: Leong CO, etal., J Clin Invest. 2007 May;117(5):1370-80. Epub 2007 Apr 19.
RGD ID: 2290583
Pubmed: PMID:17446929   (View Abstract at PubMed)
PMCID: PMC1849987   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI30866   (Journal Full-text)

Breast cancers lacking estrogen and progesterone receptor expression and Her2 amplification exhibit distinct gene expression profiles and clinical features, and they comprise the majority of BRCA1-associated tumors. Here we demonstrated that the p53 family member p63 controls a pathway for p73-dependent cisplatin sensitivity specific to these "triple-negative" tumors. In vivo, DeltaNp63 and TAp73 isoforms were coexpressed exclusively within a subset of triple-negative primary breast cancers that commonly exhibited mutational inactivation of p53. The DeltaNp63alpha isoform promoted survival of breast cancer cells by binding TAp73 and thereby inhibiting its proapoptotic activity. Consequently, inhibition of p63 by RNA interference led to TAp73-dependent induction of proapoptotic Bcl-2 family members and apoptosis. Breast cancer cells expressing DeltaNp63alpha and TAp73 exhibited cisplatin sensitivity that was uniquely dependent on TAp73. Thus, in response to treatment with cisplatin, but not other chemotherapeutic agents, TAp73 underwent c-Abl-dependent phosphorylation, which promoted dissociation of the DeltaNp63alpha/TAp73 protein complex, TAp73-dependent transcription of proapoptotic Bcl-2 family members, and apoptosis. These findings define p63 as a survival factor in a subset of breast cancers; furthermore, they provide what we believe to be a novel mechanism for cisplatin sensitivity in these triple-negative cancers, and they suggest that such cancers may share the cisplatin sensitivity of BRCA1-associated tumors.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TP73Humantriple-receptor negative breast cancer  IEP mRNA:increased expression:breastRGD 
Tp73Rattriple-receptor negative breast cancer  ISOTP73 (Homo sapiens)mRNA:increased expression:breastRGD 
Trp73Mousetriple-receptor negative breast cancer  ISOTP73 (Homo sapiens)mRNA:increased expression:breastRGD 

Objects Annotated

Genes (Rattus norvegicus)
Tp73  (tumor protein p73)

Genes (Mus musculus)
Trp73  (transformation related protein 73)

Genes (Homo sapiens)
TP73  (tumor protein p73)


Additional Information