Abstract P3-03-13: Chronic inhibition of signal transducer and activator of transcription 3/5 in treatment-resistant human breast cancer cell subtypes: Convergence on the reactive oxyten species/SUMOylation pathway and its effects on xCT expression and system xc- activity
Bibliographic record
Abstract
Abstract Pharmacologically targeting activated signal transducer and activator of transcription 3 (STAT3) and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter system xc- contributes to redox balance and export of intracellularly produced glutamate in response to up-regulated glutaminolysis in aggressive breast cancer cells. We have previously shown that blocking STAT3/5 using the novel small molecule inhibitor SH-4-54, designed to target the SH2 domains of both proteins, increases expression of xCT, which encodes the active component of system xc-, thereby increasing antiporter activity in human breast cancer cells. The current investigation demonstrates that chronic treatment with SH-4-54, followed by clonal selection of treatment-resistant MDA-MB-231 and T47D breast cancer cells, elicits distinct subtype-dependent effects. xCT mRNA and protein levels, glutamate release, and cystine uptake are decreased relative to untreated passage-matched controls in the triple-negative MDA-MB-231 SH-4-54-resistant clones, with the inverse occurring in estrogen-responsive T47D cells. This “ying-yang” effect is linked with a shifted balance between phosphorylated STAT3 and STAT5, intracellular levels of reactive oxygen species (ROS), STAT5 SUMOylation/de-SUMOylation, and the expression of STAT3/5 target genes (assessed by NextGeneration RNA sequencing). STAT5 emerged as a definitive negative transcriptional regulator of xCT, while STAT3 activation was coupled with increased system xc- activity. Specifically, inhibiting constitutive STAT3 phosphorylation in MDA-MB-231 cells induces ROS, thereby affecting the SUMO pathway by favoring de-SUMOylation and STAT5 phosphorylation. Activated STAT5 is then able to serve as a repressor by binding to its recognition sequence within the xCT promoter, reducing xCT expression and thereby destabilizing an important redox balancing mechanism by limiting cystine uptake through system xc-. In contrast, in ERα-positive cells that initially respond to STAT5-mediated signaling, STAT3 becomes activated and xCT expression is up-regulated in response to chronic SH-4-54 treatment, potentially leading to a more aggressive cancer subtype. Further destabilizing the cellular redox status may therefore be critical to produce clinically meaningful outcomes linked to chronic treatment with potent STAT3/5 inhibitors like SH-4-54. We assessed this notion by treating SH-4-54-resistant MDA-MB-231 clones with specific ROS-inducing reagents, including capsazepine, bleomycin, and paclitaxel, which produced different effects on cell viability. We propose that careful classification of a patient's breast cancer subtype is central to therapeutically targeting STAT3/5 as a means of treating breast cancer, particularly given that xCT is emerging as an important biomarker of aggressive cancers. Citation Format: Linher-Melville K, Nashed MG, Ungard R, Haftchenary S, Gunning PT, Singh G. Chronic inhibition of signal transducer and activator of transcription 3/5 in treatment-resistant human breast cancer cell subtypes: Convergence on the reactive oxyten species/SUMOylation pathway and its effects on xCT expression and system xc- activity [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-13.
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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) | 0.003 | 0.001 |
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".