Investigation of HDAC inhibition targeting of BRCA1 expression as a mechanism to enhance platinum sensitivity in breast and ovarian cancer
Bibliographic record
Abstract
e22017 Background: The improved outcome of Breast-Cancer 1 (BRCA1)-deficient breast and ovarian cancer may be linked to the impaired ability to repair double strand breaks caused by DNA-damaging chemotherapy (CTX), such as platinum compounds. Therapeutically relevant agents that target BRCA1 expression to sensitize tumors to platinum have not been identified. In this study, we explore the effect of histone deacetylase inhibition (HDACi) on platinum sensitivity and BRCA1 expression in a breast and ovarian cancer cell line model. Methods: The efficacy of HDACi to potentiate the cytotoxicity of platinum-based chemotherapeutics was evaluated in a range of breast and ovarian tumor cell lines using the MTT cell viability assay and confirmed by flow cytometry. BRCA1 mRNA and protein expression was determined by Q-PCR and Western blot, respectively. The effect on DNA damage was measured by immunofluorescence staining and flow cytometry for γH2A.X foci, a hallmark for the presence of DNA double strand breaks. Results: Baseline BRCA1 expression was variable in two ovarian (A2780s, cisplatin-sensitive and A2780cp, cisplatin-resistant) and four breast cancer cell lines (MCF7, T47D, BT549 and HCC1937) with minimal and absent protein expression in BT549 and HCC1937, respectively. The addition of the HDACi, M344 increased the sensitivity of cells to cisplatin and carboplatin treatment in those cell lines with significant BRCA1 levels. Expression of BRCA1 protein decreased in response to the addition of HDACi to platinum in all cell lines. BRCA1 mRNA levels decreased with the addition of HDACi to platinum in all breast cancer lines and in A2780cp. A2780s and MCF7 cells subjected to combination platinum and HDACi treatment demonstrated increased levels of DNA damage, as assessed by the presence of phosphorylated γH2A.X foci. Conclusions: This study supports a novel mechanism of HDAC inhibition to sensitize breast and ovarian cancer cells to platinum via inhibition of the DNA repair protein BRCA1. BRCA1 expression changes may represent a novel biomarker to assess the activity of this combinational therapeutic approach in clinical evaluations of breast and ovarian cancer patients. No significant financial relationships to disclose.
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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".