Canonical <scp>Kaiso</scp> target genes define a functional signature that associates with breast cancer survival and the invasive lobular carcinoma histological type
Bibliographic record
Abstract
Abstract Invasive lobular carcinoma (ILC) is a low‐ to intermediate‐grade histological breast cancer type caused by mutational inactivation of E‐cadherin function, resulting in the acquisition of anchorage independence (anoikis resistance). Most ILC cases express estrogen receptors, but options are limited in relapsed endocrine‐refractory disease as ILC tends to be less responsive to standard chemotherapy. Moreover, ILC can relapse after >15 years, an event that currently cannot be predicted. E‐cadherin inactivation leads to p120‐catenin‐dependent relief of the transcriptional repressor Kaiso (ZBTB33) and activation of canonical Kaiso target genes. Here, we examined whether an anchorage‐independent and ILC‐specific transcriptional program correlated with clinical parameters in breast cancer. Based on the presence of a canonical Kaiso‐binding consensus sequence (cKBS) in the promoters of genes that are upregulated under anchorage‐independent conditions, we defined an ILC‐specific anoikis resistance transcriptome (ART). Converting the ART genes into human orthologs and adding published Kaiso target genes resulted in the Kaiso‐specific ART (KART) 33‐gene signature, used subsequently to study correlations with histological and clinical variables in primary breast cancer. Using publicly available data for ER POS Her2 NEG breast cancer, we found that expression of KART was positively associated with the histological ILC breast cancer type ( p < 2.7E‐07). KART expression associated with younger patients in all invasive breast cancers and smaller tumors in invasive ductal carcinoma of no special type (IDC‐NST) (<2 cm, p < 6.3E‐10). We observed associations with favorable long‐term prognosis in both ILC (hazard ratio [HR] = 0.51, 95% CI = 0.29–0.91, p < 3.4E‐02) and IDC‐NST (HR = 0.79, 95% CI = 0.66–0.93, p < 1.2E‐04). Our analysis thus defines a new mRNA expression signature for human breast cancer based on canonical Kaiso target genes that are upregulated in E‐cadherin deficient ILC. The KART signature may enable a deeper understanding of ILC biology and etiology. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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How this classification was reachedexpand
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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".