PO-060 ErbB2/Her2-dependent downregulation of a transcription factor IRF6 in breast cancer cells is required for their three-dimensional growth
Bibliographic record
Abstract
Introduction The ability to resist anoikis, a form of apoptosis triggered by detachment of non-malignant epithelial cells from the extracellular matrix (ECM), is thought to be critical for breast tumour invasion and metastasis. ErbB2/Her2, an oncoprotein often overproduced by breast cancer cells, blocks anoikis of breast cancer cells via mechanisms that are not well understood. Our goal is to understand these mechanisms. Material and methods We studied the expression of a transcription factor Irf6, an important mediator of the mammary gland homeostasis, in non-malignant breast epithelial cells MCF-10A and non-malignant primary human mammary epithelial cells (HMEC) before and after their detachment from the ECM. We also examined Irf6 expression in detached ErbB2-overproducing breast cancer cells. We used small interfering RNAs (siRNAs) to knock down Irf6 in the non-malignant cells, infected breast tumour cells with an Irf6-encoding retrovirus to overexpress Irf6 and measured detachment-induced apoptosis of the cells before and after the indicated changes in Irf6 expression. Results and discussions We found that detachment of MCF-10A or HMEC cells upregulates Irf6 and that Irf6 upregulation promotes their anoikis. We established that ErbB2 downregulates Irf6 in detached breast cancer cells. We also found that an anti-ErbB2 antibody trastuzumab and a small molecule ErbB2 inhibitor lapatinib used for ErbB2-positive breast cancer treatment upregulate Irf6 in ErbB2-overproducing detached human breast cancer cells but not in the isogenic variants of these cells selected for, respectively, trastuzumab and lapatinib resistance. Moreover, we demonstrated that ectopic Irf6 causes anoikis of ErbB2-overproducing breast cancer cells and blocks their anchorage-independent growth. We found that the effect of ErbB2 on Irf6 requires the activity of a protein kinase Mek, a mediator of ErbB2 signalling. We also observed that detachment-induced Irf6 upregulation in MCF10A cells is mediated by a transcription factor deltaNp63 and that deltaNp63 expression is blocked by ErbB2 or an activated Mek mutant in detached ErbB2-overexpressing breast cancer cells. Conclusion Our data indicate that deltaNp63-dependent Irf6 upregulation causes anoikis of non-malignant breast epithelial cells, and that ErbB2/Mek-driven deltaNp63 downregulation and the resulting Irf6 loss blocks this anoikis. Thus, we have identified a novel mechanism by which ErbB2, a major oncoprotein, promotes anchorage-independent growth of breast cancer cells.
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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) | 0.000 | 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) | 0.004 | 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".