Dual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states
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Bibliographic record
Abstract
Triple‐negative breast cancer ( TNBC ), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer‐related deaths. This is largely due to cancer plasticity and the development of cancer stem cells ( CSC s). Recently, distinct yet interconvertible mesenchymal‐like and epithelial‐like states have been revealed in breast CSC s. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/β‐catenin and Hippo/ YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/β‐catenin and Hippo/ YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD 44 high / CD 24 −/low CSC s were upregulated while Wnt/β‐catenin signaling and ALDH + CSC s were downregulated in mesenchymal‐like TNBC cells, and vice versa in their epithelial‐like counterparts. Dual knockdown of YAP and Wnt/β‐catenin, but neither alone, was required for effective suppression of both CD 44 high / CD 24 −/low and ALDH + CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG ‐001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD 44 expression in patients’ samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD 44 high / CD 24 −/low and ALDH + CSC subpopulations were diminished in a human xenograft model after dual administration of ICG ‐001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new therapeutic strategy for TNBC via dual Wnt and YAP inhibition.
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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 | 0.000 | 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it