BRCA1/ATF1-Mediated Transactivation is Involved in Resistance to PARP Inhibitors and Cisplatin
Bibliographic record
Abstract
Homologous recombination (HR)-deficient cells are sensitive to PARP inhibitors through a synthetic lethal effect. We previously developed an HR activity assay named Assay of Site-Specific HR Activity (ASHRA). Here, we evaluated the HR activity of 30 missense variants of BRCA1 by ASHRA and found that several BRCA1 variants showed intermediate HR activity, which was not clearly discerned by our previous analyses using a conventional method. HR activity measured by ASHRA was significantly correlated with sensitivity to olaparib. However, cells expressing the severely HR-deficient BRCA1-C61G variant were resistant to olaparib, and resistance was dependent on high expression of activating transcription factor 1 (ATF1), which binds to BRCA1 and activates the transcription of target genes to regulate cell proliferation. The BRCA1-C61G variant bound to ATF1 and stimulated ATF1-mediated transactivation similar to wild-type BRCA1. High expression of ATF1 conferred resistance to olaparib and cisplatin activating BRCA1/ATF1-mediated transcription without affecting HR activity in BRCA2-knockdown or RAD51-knockdown cells, but not in BRCA1-knockdown cells. These results suggest that ASHRA is a useful method to evaluate HR activity in cells and to predict the sensitivity to PARP inhibitors. The expression level of ATF1 might be an important biomarker of the effect of PARP inhibitors and platinum agents on HR-deficient tumors with the BRCA1-C61G variant or alteration of non-BRCA1 HR factors such as BRCA2 and RAD51. Significance: ASHRA could evaluate HR activity in cells and predict the sensitivity to PARP inhibitors. High expression level of ATF1 may predict the resistance of BRCAness tumors with alterations of non-BRCA1 HR factors to PARP inhibitors and platinum agents.
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".