Abstract P5-18-08: Identification of ErbB2 function in the heart: implication for anti-ErbB2 therapy in breast cancer
Bibliographic record
Abstract
Abstract The ErbB2 receptor tyrosine kinase is essential for cardiac development during embryogenesis. The importance of its signaling in the adult heart was revealed by an unexpected cardiotoxic side effect of trastuzumab, a monoclonal antibody against ErbB2 used in the treatment of breast cancer. Considering that trastuzumab-associated cardiotoxicity is usually largely reversible, we hypothesized that ErbB2 signaling in the heart is important to maintain cardiac homeostasis. As genetic experiments showed that ErbB2-deficient embryos die at mid-gestation, whereas conditional inactivation of ErbB2 in the heart leads to early and severe cardiac dysfunction, the role of ErbB2 in the mature heart can not be analyzed in those animal models. Thus, we chose an ErbB2 hypomorph (HP) mouse model in which ErbB2 is expressed at only 10% of its endogenous level to study the role of ErbB2 in the adult heart. Histopathological analyses of the heart in this model revealed that at birth, the ErbB2 HP mice have similar heart mass and cardiomyocite size as the control animals. However, we found that the rapid growth of the heart during early postnatal development is impaired in ErbB2 HP mice, indicating that the heart is unable to increase cell size in order to adapt to the pressure overload that mice face following birth. This incapacity of the ErbB2 HP heart to maintain homeostasis eventually leads to the development of cardiac dysfunction in this model, as characterized by a decrease of the left ventricular function. Microarray and ChIP-seq analyses were applied to identify the ErbB2-responsive pathways which may explain the phenotype observed. Taken together, our results demonstrate that ErbB2 signaling is required for the physiological adaptive response of the mature heart to pressure burden. The results generated by this study reveal the biological function of Erbb2 in the adult heart, but also provide important information for devising strategies to prevent and mitigate the cardiotoxic effects of Trastuzumab treatment, allowing for the potential use of this drug to treat all cancer patients overexpressing ErbB2. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-08.
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".