title: PTEN deletion in prostate cancer cells does not associate with loss of RAD51 function: implications for radiotherapy and chemotherapy.
abstract: OBJECTIVE
  PTEN deletions in prostate cancer are associated with tumor aggression and poor outcome. Recent studies have implicated PTEN as a determinant of homologous recombination (HR) through defective RAD51 function. Similar to BRCA1/2-defective tumor cells, PTEN-null prostate and other cancer cells have been reported to be sensitive to PARP inhibitors (PARPi). To date, no direct comparison between PTEN and RAD51 expression in primary prostate tumors has been reported.
  
  
  METHODS
  Prostate cancer cell lines and xenografts with known PTEN status (22RV1-PTEN(+/+), DU145-PTEN(+/-), PC3-PTEN(-/-)) and H1299 and HCT116 cancer cells were used to evaluate how PTEN loss affects RAD51 expression and PARPi sensitivity. Primary prostate cancers with known PTEN status were analyzed for RAD51 expression.
  
  
  RESULTS
  PTEN status is not associated with reduced RAD51 mRNA or protein expression in primary prostate cancers. Decreased PTEN expression did not reduce RAD51 expression or clonogenic survival following PARPi among prostate cancer cells that vary in TP53 and PTEN. PARPi sensitivity instead associated with a defect in MRE11 expression. PTEN-deficient cells had only mild PARPi sensitivity and no loss of HR or RAD51 recruitment. Clonogenic cell survival following a series of DNA damaging agents was variable: PTEN-deficient cells were sensitive to ionizing radiation, mitomycin-C, UV, H(2)O(2), and methyl methanesulfonate but not to cisplatin, camptothecin, or paclitaxel.
  
  
  CONCLUSIONS
  These data suggest that the relationship between PTEN status and survival following DNA damage is indirect and complex. It is unlikely that PTEN status will be a direct biomarker for HR status or PARPi response in prostate cancer clinical trials.
authors: Ontario Cancer Institute/Princess Margaret Hospital (University Health Network), University of Toronto, Toronto, Canada.
authors: Michael
authors: M
authors: Fraser
authors: Helen
authors: H
authors: Zhao
authors: Kaisa R
authors: KR
authors: Luoto
authors: Cecilia
authors: C
authors: Lundin
authors: Carla
authors: C
authors: Coackley
authors: Norman
authors: N
authors: Chan
authors: Anthony M
authors: AM
authors: Joshua
authors: Tarek A
authors: TA
authors: Bismar
authors: Andrew
authors: A
authors: Evans
authors: Thomas
authors: T
authors: Helleday
authors: Robert G
authors: RG
authors: Bristow
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D000076228:MRE11 Homologue Protein; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C121766:MRE11 protein, human; D015514:Oncogene Proteins, Fusion; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C515553:TMPRSS2-ERG fusion protein, human; D051135:Rad51 Recombinase; D000076228:MRE11 Homologue Protein; D051059:PTEN Phosphohydrolase