Response of breast cancer cell lines to aminoflavone (NSC 686288) is associated with histone H2AX phosphorylation and estrogen receptor expression
Bibliographic record
Abstract
555 Aminoflavone (AF; 5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one; NSC 686288) is a novel anticancer agent which has entered early clinical trials sponsored by the US-National Cancer Institute. AF has shown exquisite sensitivity toward a limited number of human tumor cell lines including lung, ovarian, renal, and breast carcinomas. AF is a ligand of the aryl hydrocarbon receptor (AhR). Its activity has been linked to the presence of cytoplasmic AhR, translocation of the AhR:AF complex to the nucleus followed by induction of cytochrome P450 (CYP) 1A1 and DNA damage caused by metabolites. The latter is exemplified by the occurrence of gamma-histone 2AX (H2AX) phosphorylation consistent with induction of DNA single-strand breaks and DNA-protein cross-links. In this study, we examined determinants of AF response in a panel of molecularly well defined breast cell lines, they include: MCF-7 (estrogen receptor positive, ER+), T47D (ER+), MCF-7/HER2-18 (ER+), MDA-MB-231 (ER-), and MCF10A (ER-). Antiproliferative effects were measured by MTT assay, and concentrations that inhibit cell growth to 50 % of control (IC50) were established for each cell line. The response to AF was compared to ER status, AhR localization, and gamma-H2AX foci formation in a time and concentration dependent manner by dual immunofluorescence labeling. We found that AF potently inhibited the growth of ER+ breast cancer cell lines at nanomolar concentrations (mean IC50s: MCF-7 = 18 nM; MCF-7/HER2-18 = 20 nM; T47D = 14 nM), whereas the ER- breast cancer cell line MDA-MB-231 (IC50 = 25 μM) and the immortalized ER- breast cell line MCF10A (IC50 = 3 μM) were several log-fold less sensitive. In cell lines that were exquisitely sensitive to AF, AhR expression was found to be more cytoplasmic than nuclear. In contrast, the cell lines resistant to AF showed a predominantly nuclear AhR localization. Gamma-H2AX foci occurred between 6 to 24 hours only in AF responsive ER+ breast cancer cells treated at their respective IC50s, but not in the ER- cell lines. Interestingly, MCF-7/HER2-18 (IC50 = 20 nM, IC100 = 375 nM), which is a HER2/neu receptor overexpressing Herceptin and tamoxifen resistant subclone of MCF-7 (IC50 4-OH-tamoxifen >1μM), retained its sensitivity to AF if compared to the parental MCF-7 cells (IC50 = 18 nM, IC100 = 300 nM). These observations suggest that AF, unlike other antineoplastic agents, requires a specific activation to cause DNA damage and that AhR and its cross talk with ER are determinates of this specific response. AF activity in Herceptin and tamoxifen resistant MCF-7 cells indicates that AF might provide a new treatment strategy for hormone-refractory ER positive breast cancers and that this hypothesis should be tested in a larger sample cohort and in vivo models.
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) | 0.000 | 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) | 0.002 | 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".