β1-Integrin Circumvents the Antiproliferative Effects of Trastuzumab in Human Epidermal Growth Factor Receptor-2–Positive Breast Cancer
Bibliographic record
Abstract
Resistance to trastuzumab, the monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), is a major concern for HER-2-positive metastatic breast cancer (MBC) patients. To date, HER-2 status is the only available biomarker for selecting patients for trastuzumab-based therapy. Beta(1)-integrin, an adhesion molecule involved in cell survival and drug resistance, shares common downstream signaling elements with HER-2, such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways. The significance of beta(1)-integrin expression in HER-2-positive breast cancer and its involvement in a patient's response to trastuzumab-based therapy are unknown. We show here that overexpression of beta(1)-integrin is an independent negative prognostic factor for tumor progression of HER-2-positive MBC patients treated with trastuzumab-based chemotherapy. Enforced overexpression of beta(1)-integrin, its small interfering RNA-induced knockdown or treatment with a beta(1)-integrin-blocking antibody in HER-2-positive breast cancer cells, identified a strong inverse relationship between expression level of beta(1)-integrin and in vitro sensitivity to trastuzumab. Notably, beta(1)-integrin overexpression increased the phosphorylation of Akt-Ser473 and ERK1/2, thereby promoting survival and mitogenic signals to bypass the antiproliferative effects of trastuzumab. Our findings show that beta(1)-integrin provides a novel independent prognostic biomarker of trastuzumab response in HER-2-positive MBC patients and suggest a new target to augment the antiproliferative effects of trastuzumab.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".