Data from <i>PTEN</i> Deletion in Prostate Cancer Cells Does Not Associate with Loss of RAD51 Function: Implications for Radiotherapy and Chemotherapy

Abstract

<div>Abstract<p><b>Purpose:</b><i>PTEN</i> deletions in prostate cancer are associated with tumor aggression and poor outcome. Recent studies have implicated <i>PTEN</i> as a determinant of homologous recombination (HR) through defective RAD51 function. Similar to <i>BRCA1/2</i>-defective tumor cells, <i>PTEN</i>-null prostate and other cancer cells have been reported to be sensitive to PARP inhibitors (PARPi). To date, no direct comparison between <i>PTEN</i> and <i>RAD51</i> expression in primary prostate tumors has been reported.</p><p><b>Experimental Design:</b> Prostate cancer cell lines and xenografts with known <i>PTEN</i> status (22RV1-<i>PTEN</i><sup>+/+</sup>, DU145-<i>PTEN</i><sup>+/−</sup>, PC3-<i>PTEN</i><sup>−/−</sup>) and H1299 and HCT116 cancer cells were used to evaluate how <i>PTEN</i> loss affects RAD51 expression and PARPi sensitivity. Primary prostate cancers with known <i>PTEN</i> status were analyzed for RAD51 expression.</p><p><b>Results:</b><i>PTEN</i> status is not associated with reduced <i>RAD51</i> mRNA or protein expression in primary prostate cancers. Decreased <i>PTEN</i> expression did not reduce <i>RAD51</i> expression or clonogenic survival following PARPi among prostate cancer cells that vary in <i>TP53</i> and <i>PTEN</i>. PARPi sensitivity instead associated with a defect in <i>MRE11</i> expression. <i>PTEN-</i>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: <i>PTEN</i>-deficient cells were sensitive to ionizing radiation, mitomycin-C, UV, H<sub>2</sub>O<sub>2</sub>, and methyl methanesulfonate but not to cisplatin, camptothecin, or paclitaxel.</p><p><b>Conclusions:</b> These data suggest that the relationship between <i>PTEN</i> status and survival following DNA damage is indirect and complex. It is unlikely that <i>PTEN</i> status will be a direct biomarker for HR status or PARPi response in prostate cancer clinical trials. <i>Clin Cancer Res; 18(4); 1015–27. ©2011 AACR</i>.</p></div>