Abstract B009: A role for receptor tyrosine kinase crosstalk in a Met-dependent model of triple-negative breast cancer
Bibliographic record
Abstract
Abstract Triple-negative (TN) breast cancers, which include the basal-like and claudin-low subtypes, account for up to 20% of breast cancer cases. TN breast cancers lack expression of therapeutic targets HER2 and estrogen receptors and are correlated with poor prognosis. In human breast cancer, elevated levels of MET are correlated with TN subtypes and poor outcome. The Met receptor tyrosine kinase (RTK) is a cell surface protein that, upon activation by its ligand hepatocyte growth factor (HGF), initiates a program of cell survival, migration, and invasive growth. To investigate the role of Met in breast tumorigenesis, we have used two mouse models in which mammary specific expression of an oncogenic variant of Met is driven by the MMTV promoter (Metmt). Metmt mice develop mammary tumors with a long latency and display features of basal-like breast cancer. As loss of function mutations in TP53 are found in ~80% of TN breast cancers, we have also generated Metmt mice with conditional deletion of Trp53 in the mammary gland (Metmt;p53-), which results in accelerated tumorigenesis and gene expression profiles that more closely resemble that of the claudin-low subtype of TN breast cancer. The present work aims to elucidate how Met promotes mammary tumor development and whether this involves regulation of tumor-initiating cells (TICs). TICs have emerged as a key concept in prevailing models of tumor development, and are thought to drive tumorigenesis as well as contribute to disease relapse. To study TICs in our mouse models, we employed the sphere-forming assay, which enriches for TICs based on their stem-like ability to survive, propagate, and self-renew in suspension as spheroid structures (tumorspheres). Tumorspheres cultured from both tumor models express constitutively active Met. Upon treatment with Met inhibitor, Metmt tumorspheres are drastically reduced in both number and size. In contrast, Metmt;p53- tumorspheres are insensitive to Met inhibition, suggesting that other signals compensate for the loss of Met activity. It has been shown that Met can crosstalk with other RTKs such as EGFR. Therefore we hypothesize that activation of an alternative RTK signalling pathway is compensating for loss of Met signalling in Metmt;p53- tumorspheres. The molecular events that lead to TN breast cancers are poorly understood. Validating a role for Met in TICs and identifying key cooperating pathways involved in the pathogenesis of triple negative breast cancers could provide information for new therapeutic targets. Citation Format: Vanessa Sung, Jennifer F. Knight, Morag Park. A role for receptor tyrosine kinase crosstalk in a Met-dependent model of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B009.
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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 | 0.001 |
| 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) | 0.002 | 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".