Abstract 3932: Loss of PTEN sensitizes cells to DNA damaging agents in a RAD51-independent manner
Bibliographic record
Abstract
Abstract The PTEN tumor suppressor gene is frequently mutated or deleted in many cancers. While the role of PTEN as an inhibitor of the PI3K/Akt signaling pathway via its intrinsic lipid phosphatase activity has been well-studied, recent data suggest that loss of PTEN contributes to genomic instability through a PI3K/Akt-independent pathway via down-regulation of E2F1-dependent transactivation of Rad51, a key mediator of homologous recombination (HR). Cells with dysfunctional HR are sensitive to inhibitors of Poly(ADP)Ribose Polymerase (PARP) and therefore PTEN loss could sensitize cells to PARP inhibitors in a RAD51-dependent manner. Using PTEN-isogenic cell lines, cells treated with siRNA to PTEN and human prostate cancer cell lines with disparate PTEN status, we assessed whether PTEN loss is associated with altered expression of RAD51 protein. We also evaluated the effects of PTEN loss on sensitivity to PARP inhibition and various DNA damaging agents which sensitize cells based on deficiency in DNA double- and single-strand break repair, nucleotide excision repair and base excision repair (i.e. ionizing radiation (IR), camptothecin (CPT), Mitomycin C, cisplatin, ultraviolet radiation (UV), H2O2 and MMS). We observed that PTEN status did not predict RAD51 expression in PTEN−/− (PC3), PTEN+/− (DU145), and PTEN+/+ (22RV1) prostate cancer cells or xenografts in vitro or in vivo. Using a dedicated tissue microarray of localized prostate cancer, PTEN status (based on FISH) did not predict for RAD51 expression. Furthermore, we observed no difference in RAD51 mRNA or protein expression nor in E2F1 binding to the RAD51 promoter in PTEN-deficient HCT116 colorectal cancer cells or H1299 lung carcinoma cells treated with siRNA to PTEN. PTEN expression also did not alter RAD51 localization to IR-induced nuclear foci or UV microirradiation-induced DNA DSBs. However, using clonogenic assays, we observed that loss of PTEN did miminally sensitize cells to PARP inhibition with increased sensitization to MMC, cisplatin, UV, and IR. PTEN loss did not sensitize tumour cells to MMS, CPT or paclitaxel. Taken together, these data suggest that PTEN influences sensitivity to certain DNA damaging agents in a RAD51-independent manner. To understand this sensitivity, we are documenting gene expression changes in 200 DNA repair and replication genes using NanoString technology. A better understanding of the influence of PTEN on cellular sensitivity to chemo- and radiotherapy may ultimately help to guide treatment options for patients based on PTEN status (Sponsored by CCSRI, PCC and the Terry Fox Foundation). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3932.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".