Abstract 18705: BRCA2 is a Novel Regulator of Endothelial Cell Function and Apoptosis
Bibliographic record
Abstract
Background: Germ-line mutations in the tumor suppressor gene BRCA2 (breast cancer 2, early onset) predispose carriers not only to breast cancer, but also to other cancers. BRCA2 plays crucial role in the genome integrity maintenance and is central to DNA-damage repair. BRCA2-associated DNA-damage responses are not only specific to cancer syndromes but also represent a common pathophysiological basis for diverse cardiovascular diseases (CVDs). These observations led us to hypothesize that BRCA2 is an essential regulator of endothelial function and apoptosis following genotoxic stress. Methods: To elucidate the role of BRCA2 in endothelial cells, we silenced BRCA2 in the human umbilical vein endothelial cells (ECs) and measured the indices of EC function; tube formation and proliferation, DNA-damage/repair and apoptosis by qPCR, immunoblotting and immunofluorescence following doxorubicin (Dox) treatment. Results: We confirmed the basal expression and successful silencing of BRCA2 in ECs at transcript and protein levels by qPCR and immunoblotting, respectively. Genotoxic stress in the form of Dox exacerbated DNA-damage in BRCA2-silenced ECs as evident by increased expression and activation of DNA double-stranded breaks (DSBs) marker H2A.X and reduced RAD51-foci formation, an essential regulator of DSB repair. Increased DSBs were associated with significantly increased expression and activation of p53, and increased expression of p53-upregulated modulator of apoptosis PUMA. Elevated levels of DNA-damage and p53 were further associated with significantly increased Dox-induced apoptosis in BRCA2-silenced ECs as measured by immunoblotting for cleaved-caspase-3 and TUNEL-staining.Key indices of endothelial function, including tube formation and proliferation, were significantly reduced following Dox-treatment in BRCA2-deficient ECs, which was accompanied with significantly increased expression of cell cycle inhibitor, p21 at transcript and protein levels. Conclusion: Our data for the first time, show an entirely novel role of BRCA2 as a regulator of endothelium, and provide important clues regarding a potential susceptibility of BRCA2 mutation carriers to anthracycline-induced CVDs, a cornerstone of chemotherapy for cancer.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".