RT Journal Article
SR Electronic
T1 PTEN Deficiency in Endometrioid Endometrial Adenocarcinomas Predicts Sensitivity to PARP Inhibitors
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 53ra75
OP 53ra75
DO 10.1126/scitranslmed.3001538
VO 2
IS 53
A1 Dedes, Konstantin J.
A1 Wetterskog, Daniel
A1 Mendes-Pereira, Ana M.
A1 Natrajan, Rachael
A1 Lambros, Maryou B.
A1 Geyer, Felipe C.
A1 Vatcheva, Radost
A1 Savage, Kay
A1 Mackay, Alan
A1 Lord, Christopher J.
A1 Ashworth, Alan
A1 Reis-Filho, Jorge S.
YR 2010
UL http://stm.sciencemag.org/content/2/53/53ra75.abstract
AB 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.