Document Detail


PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors.
MedLine Citation:
PMID:  20944090     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PTEN (phosphatase and tensin homolog) loss of function is the most common genetic aberration in endometrioid endometrial carcinomas. In addition to its well-described role in cell signaling, PTEN is involved in the maintenance of genomic stability. Loss of PTEN function causes defects in repair of DNA double-strand breaks by homologous recombination and, therefore, sensitizes cells to inhibition of the poly(adenosine diphosphate ribose) polymerase (PARP). Here, we determined the PTEN status of eight endometrioid endometrial carcinoma cell lines and correlated it with in vitro sensitivity to the PARP inhibitor KU0058948. PTEN-deficient cells showed a significantly greater sensitivity to KU0058948 than the two endometrioid endometrial carcinoma cell lines with wild-type PTEN. The cell lines lacking PTEN expression were unable to elicit a homologous recombination damage response as assayed by RAD51 focus function (a marker of competent homologous recombination DNA repair) upon irradiation and treatment with PARP inhibitors. PTEN silencing in PTEN wild-type Hec-1b cells resulted in reduced RAD51 foci formation after DNA damage and increased sensitivity to PARP inhibition. PTEN reexpression in PTEN-null cell lines resulted in enhanced RAD51 foci formation and in relative resistance to KU0058948. Given that up to 80% of endometrioid endometrial cancers lack PTEN expression, our results suggest that PARP inhibitors may be therapeutically useful for a subset of endometrioid endometrial cancers.
Authors:
Konstantin J Dedes; Daniel Wetterskog; Ana M Mendes-Pereira; Rachael Natrajan; Maryou B Lambros; Felipe C Geyer; Radost Vatcheva; Kay Savage; Alan Mackay; Christopher J Lord; Alan Ashworth; Jorge S Reis-Filho
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science translational medicine     Volume:  2     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-14     Completed Date:  2011-01-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  53ra75     Citation Subset:  IM    
Affiliation:
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, SW3 6JB London, UK.
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MeSH Terms
Descriptor/Qualifier:
Carcinoma, Endometrioid / drug therapy*,  genetics*
Cell Line, Tumor
DNA Mutational Analysis
Drug Resistance, Neoplasm / genetics
Endometrial Neoplasms / drug therapy*,  genetics*
Enzyme Inhibitors / therapeutic use
Female
Fluorobenzenes / therapeutic use
Humans
In Situ Hybridization, Fluorescence
PTEN Phosphohydrolase / deficiency*,  genetics
Phthalazines / therapeutic use
Poly(ADP-ribose) Polymerases / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Fluorobenzenes; 0/KU0058948; 0/Phthalazines; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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