Gamma-Secretase, ErbB4 nuclear localization and neuregulin expression correlates with prostate cancer patient clinical outcome
Bibliographic record
Abstract
10587 Background: Membrane protein ErbB4 is a member of ErbB growth factor receptor family, which can be activated by neuregulins (NRG). Upon neuregulin activation, ErbB4 is cleaved within its transmembrane domain by presenilin γ-secratase (PSN) to release an intracellular domain that translocates into the nucleus. Although, ErbB4 ligand-dependant translocation of ErbB4 to the nucleus and its nuclear activity has been reported in breast cancer cell lines, there are few reports concerning ErbB4 nuclear localization and its clinical relevance. Here, we report for the first time the clinical relevance of ErbB4 nuclear localization, NRG, and PSN expression in prostate cancer tissues. Methods: Immunostaining using anti-ErbB4, anti-PSN2 and anti-neuregulin antibodies was done on a set of tissue microarrays (TMA) from 140 patients. The TMAs contained, 92 cores of normal prostate tissue obtained from 46 autopsy specimens from young males, 373 tumor and normal adjacent cores from 63 hormone sensitive PCa (HSPCa) patients, and 146 cores from 31 hormone refractory PCa (HRPCa) patients. Results: We found a statistically significant increase (p<0.01) in the percentage of ErbB4 nuclear localization (68.7% vs 53.2%), NRG expression (2.06 vs 1.41) and PSN2 expression (2.14 vs 1.53) when comparing cancerous tissues to normal tissue adjacent to cancer. Interestingly, a similar statistically significant increase in nuclear ErbB4 and NRG expression was observed when comparing HRPCa to HSPCa (p<0.001). In cancerous tissues, a strong correlation was found between nuclear ErbB4 and NRG expression (r=0.672), between nuclear ErbB4 and PSN2 expression (r=0.51), and between PSN2 and NRG expression (r=0.71). Nuclear ErbB4 and PSN2 inversely correlated with tumor stage and lymph node invasion. Kaplan Meier analysis of nuclear ErbB4 (p=0.030) and PSN2 expression (p=0.018) showed an inverse association with biochemical recurrence (BCR) of PCa. In multivariate analyses including these three markers and clinical parameters, only nuclear ErbB4 retained an independent prognosis value. Conclusion: Our results suggest that high nuclear ErbB4 along with increased PSN2 expression have a protective effect against prostate cancer progression and BCR. No significant financial relationships to disclose.
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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 | 0.001 |
| 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) | 0.003 | 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".