Molecular Alterations and Putative Therapeutic Targeting of Planar Cell Polarity Proteins in Breast Cancer
Bibliographic record
Abstract
Background: Treatment and outcomes of breast cancer, one of the most prevalent female cancers, have improved in recent decades. However, metastatic breast cancer remains incurable in most cases, and new therapies are needed to ameliorate prognosis. Planar cell polarity (PCP) is a characteristic of epithelial cells that form layers and is integral to the communication of these cells with neighboring cells. Dysfunction of PCP is observed in cancers and may confer a targetable vulnerability. Methods: The breast cancer cohorts from The Cancer Genome Atlas (TCGA) and the METABRIC study were interrogated for molecular alterations in genes of the PCP pathway. The groups with the most prevalent alterations were characterized, and survival was compared with counterparts not possessing PCP alterations. Breast cancer cell lines with PCP alterations from the Cancer Cell Line Encyclopedia (CCLE) were interrogated for sensitivity to drugs affecting PCP. Results: Among genes of the PCP pathway, VANGL2, NOS1AP and SCRIB display amplifications in a sizable minority of breast cancers. Concomitant up-regulation at the mRNA level can be observed mostly in basal cancers, but it does not correlate well with the amplification status of the genes, as it can also be observed in non-amplified cases. In an exploration of cell line models, two of the four breast cancer cell line models with amplifications in VANGL2, NOS1AP and SCRIB display sensitivity to drugs inhibiting acyl-transferase porcupine interfering with the WNT pathway. This sensitivity suggests a possible therapeutic role of these inhibitors in cancers bearing the amplifications. Conclusion: Molecular alterations in PCP genes can be observed in breast cancers with a predilection for the basal sub-type. An imperfect correlation of copy number alterations with mRNA expression suggests that post-translational modifications are important in PCP regulation. Inhibitors of acyl-transferase porcupine may be rational candidates for combination therapy development in PCP-altered breast cancers.
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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 | 0.001 | 0.001 |
| 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".