A novel clinically relevant antagonistic interplay between prolactin and oncogenic YAP-CCN2 pathways as a differentiation therapeutic target in breast cancer
Bibliographic record
Abstract
Cellular differentiation limits cellular plasticity allowing cells to attain their specialized functional characteristics and phenotypes, whereas loss of differentiation is a hallmark of cancer. Thus, characterizing mechanisms underlying differentiation is key to discover new cancer therapeutics. We report a novel functional antagonistic relationship between the prolactin (PRL)/prolactin receptor (PRLR) differentiation pathway and YAP-CCN2 oncogenic pathway in normal mammary epithelial cells and breast cancer cells that is essential for establishing/maintaining acinar morphogenesis, cell-cell junctions and the intracellular localization of apical-basal polarity protein complexes (Par, Crumb and Scrib). Importantly, using CRISPR knockout of the PRLR in MCF7, HR+ breast cancer cells, further revealed that the negative relationship between PRL/PRLR pathway and YAP-CCN2 pathway is critical in suppressing luminal-to-basal stem-like lineage plasticity. Furthermore, the clinical relevance of this interplay was evaluated using bioinformatics approaches on several human datasets, including samples from normal breast epithelium, breast cancer, and 33 other cancer types. This analysis revealed a positive correlation between PRLR and the YAP suppressor Hippo pathway and a co-expression gene network driving favourable patients' survival outcomes in breast cancer. The therapeutic potential of this interplay was also evaluated in vitro using MDA-MB-231 cells, a preclinical model of human triple-negative breast cancer, where treatment with PRL and Verteporfin, an FDA-approved pharmacological YAP-inhibitor, alone or their combination suppressed the expression of the mesenchymal marker vimentin and the stem cell marker CD44 as well as reduced their Ki67 proliferative marker expression. Collectively, our results emphasize the pro-differentiation role of PRL/PRLR pathway in mammary and breast cancer cells and highlight that promoting PRL/PRLR signaling while inhibiting the YAP-CCN2 oncogenic pathway can be exploited as a differentiation-based combination therapeutic strategy in breast cancer.
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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 | 0.000 |
| 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 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".