Abstract 1253: Fer is required for mammary tumorigenesis
Bibliographic record
Abstract
Abstract Fer is a ubiquitously expressed cytoplasmic protein-tyrosine kinase (PTK) which is inducibly activated upon engagement of the epidermal and platelet-derived growth factor receptors (EGFR/PDGFR). Fer - and its homologous family member Fps/Fes - are structurally distinguished from other PTKs by a membrane-binding F-BAR domain implicated in regulating membrane-cytoskeletal dynamics during receptor endocytosis. We are investigating the role of Fer in EGFR internalization using both non-transformed mammary epithelial cells (MCF10A) and mammary tumor epithelial cells (MTEC) isolated from an ErbB2 mouse model of breast cancer. MCF10A Fer-knockdown cells (MCF10A-F2) and MTECs harboring a kinase-inactivating knock-in mutation at the fer locus (ferDR/DR) displayed elevated rates of EGF-induced endocytosis suggesting that Fer inhibits EGFR internalization. Elevated endocytic rates correlated with enhanced short-term MAPK signaling in both cell culture models and elevated steady-state Erk activity in ferDR/DR ErbB2 mammary tumors. Systems-level analyses using a physiochemical model of EGFR-MAPK signaling suggested that up-regulation of receptor endocytic rates could potentiate MAPK signal strength and sensitize this pathway to pharmacological inhibition at the receptor level. Inhibition of MAPK signaling with the EGFR/ErbB2 inhibitor, Lapatinib, confirmed this prediction, showing increased Erk signal-sensitivity to this drug in endocytosis-enhanced ferDR/DR MTECs. This correlated with a 10-fold reduction in the EC50 for Lapatinib cytotoxicity on ferDR/DR MTECs. Both the signaling and cytotoxicity phenoytypes were reversible by rescued expression of wild type Fer in ferDR/DR MTECs. These data reveal a novel mechanism by which potentiation of EGFR endocytosis enhances the sensitivity of downstream signaling to inhibition by ErbB inhibitors. In this respect, Fer is a unique kinase target because it provides a direct means of pharmacologically intervening with the mechanism of EGFR endocytosis. The therapeutic significance of potentiating receptor endocytosis by targeting Fer is highlighted by observations of: (1) delayed onset of ErbB2-mediated breast tumorigenesis in ferDR/DR genetic backgrounds in vivo; and; (2) impaired tumor growth of Fer-deficient MDA-MB-231 cells in mammary-fat pad transplantation models. We envisage that anti-Fer based treatments may sensitize breast - and potentially other carcinoma types - to anti-ErbB therapies. These observations provide biological proof-in-principle for developing small molecule inhibitor-based therapies against Fer in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1253. doi:1538-7445.AM2012-1253
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.004 |
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".