Abstract 1458: The PAX5 transcription factor is a suppressor of NFAT-mediated breast cancer aggressivity
Bibliographic record
Abstract
Abstract Breast cancer metastasis is responsible for 90% of deaths associated with the disease. The understanding of mechanisms driving metastasis is thus vital to mitigate mortality rates and improve patient outcome. One of these mechanisms essential for breast cancer malignancy is the activation of the Nuclear Factor of Activated T cells (NFAT) pathway. Recently, we have reported that the PAX5 transcription factor induces breast cancer cell epithelialization, which in turn extinguishes mesenchymal transitioning, malignant features, and tumor progression. Our preliminary findings also suggests that PAX5 may negatively regulate NFAT-dependant pathways to modulate breast processes and potentially disease progression. We therefore hypothesized that PAX5 suppressed breast cancer malignancy through the targeted inhibition of the pro-malignant NFAT pathway. Using breast cancer cell models, we conditionally modulated PAX5 levels by transfection and recombinant expression to characterize PAX5-induced inhibition of the NFAT activation pathway and its mechanisms of action. Technically, expression levels for NFAT members (1 to 5) and their regulators (ex: calcium mobilization, specific kinases, and phosphatases) were assessed using RT-qPCR and Western blotting. NFAT activation was also studied through the analysis of cellular compartmentalization, reporter gene assays, and microscopy. We observed that PAX5 suppressed overall NFAT-dependant transcriptional activity in breast cancer cells through various mechanisms depending on the type of breast cancer models. We also found that although elevated PAX5 expression levels do not alter total NFAT protein levels, PAX5 affects the phosphorylation status of NFAT (activation) through the regulation of NFAT-specific phosphatases and kinases controlling NFAT import and downstream transactivation pro-malignant genes. We also found that PAX5 modulates intracellular calcium mobilization, which is also essential for NFAT activation. Altogether, our findings demonstrate that PAX5 is a potent inhibitor of NFAT-dependant processes essential for in breast cancer malignancy. Interestingly, PAX5-mediated suppression of the NFAT pathway in breast cancer cells is elicited by multiple regulatory mechanisms, which also depend on breast cancer cell type. These studies provide new insight into the molecular pathways governing breast malignancy and disease progression. Further understanding of these mechanisms of action will build the future roadmaps for therapeutic and prognostic interventions. Citation Format: Félix Després, Damien Robichaud, Brandon Hannay, Gilles A. Robichaud. The PAX5 transcription factor is a suppressor of NFAT-mediated breast cancer aggressivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1458.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 teacher head, 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".