Abstract 1949: Caspase 3 plays a requisite role in regulating survival of human breast cancer cells
Bibliographic record
Abstract
Abstract Caspase-3 has long been recognized for its key role as a protease that mediates the degradation of cellular components during the late stages of apoptosis. However, there is also a growing body of evidence that caspase-3 has essential intrinsic functions in regulating normal and malignant cell properties that are distinct from its apoptotic functions. In a previous study, we showed that a readily detectable but low proportion of freshly isolated normal human mammary cells with a luminal phenotype and a capacity to divide in vitro display a reversible expression of activated caspase-3, and subsequently it was found that suppression of caspase-3 expression in the MDA-MB-231 human breast cancer cell line contributes to its radiation-induced loss of proliferative activity in vitro. To further investigate the role of caspase-3 in normal and malignant human mammary cells, we constructed shRNA-caspase-3 and control lentiviral vectors to examine the effect of decreasing caspase-3 expression (2-fold determined by Western blot) in normal and transformed human mammary cell types. Knockdown (KD) of caspase-3 expression in 2 breast cancer cell lines (MDA-MB-231 and MCF7 cells) showed that caspase-3 KD suppressed their growth in vitro 5-fold within 8 days and inhibited formation of tumors in highly immunodeficient (NRG) adult female mice transplanted subcutaneously with shCaspase-3-transduced cells in contrast to controls in which 1cm diameter tumors appeared within 6 weeks. The shCaspase-3-transduced cells also showed a complete loss of lung metastasizing activity in intravenously injected mice. A similar anti-tumorigenic effect was also obtained in freshly isolated normal human mammary cells that were co-transduced with the shCaspase-3 vector as well as KRASG12D which otherwise causes the normal cells to produce invasive ductal carcinomas in subcutaneously transplanted immunodeficient mice. Annex V and propidium iodide staining of single-cell, as well as bulk cultures of the MDA-MB-231cells, showed that Caspase-3 is required for their survival as well as their growth. Surprisingly, initial parallel experiments with purified basal and luminal progenitor subsets of normal human mammary cells and the immortalized but non-tumorigenic MCF-10A cell line also indicates a significant suppression of cell growth in vitro within 10 days. These findings highlight the multiplicity of pro- as well as anti-survival activities that Caspase-3 exerts on normal and malignant human mammary cells raising important considerations of any therapy designed to augment their activity. Keywords: Breast cancer, Caspase-3, Cell survival Citation Format: Ebrahim Eskandari, Connie J. Eaves, Susanna Tan. Caspase 3 plays a requisite role in regulating survival of human breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1949.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".