Abstract A65: ShcA is required for the TGFβ-induced repression of Chordin-like-1 in ErbB2-expressing breast cancer cells
Bibliographic record
Abstract
Abstract Clinical data and transgenic mouse models have provided clear evidence of a critical role for the adaptor protein ShcA in mammary tumor formation and metastasis downstream of several oncogenes. Indeed, we have demonstrated that stable silencing of ShcA expression in ErbB2-expressing breast cancer cells impairs tumor outgrowth and metastasis in vivo. In addition, we have identified a requirement for an intact PTB domain and the three tyrosine residues in ShcA for mediating TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. Together, these observations position the ShcA adaptor as an important signaling node that facilitates cooperation between the ErbB2 and TGFβ signaling pathways in breast cancer progression. To understand how ShcA signaling contributes to TGFβ-induced gene expression changes, we generated a doxycycline-inducible system to deplete ShcA levels from ErbB2-expressing breast cancer cells. The inducible silencing of ShcA in pre-established ErbB2-positive tumors resulted in impaired tumor cell proliferation and survival in vivo. Gene expressing profiling was then performed on cells with an inducible loss of ShcA expression to identify ShcA-dependent transcriptional responses downstream of active TGFβ and ErbB2 signaling in breast cancer cells. ShcA was found to mediate the suppression of Chordin-like 1, a BMP antagonist. Conditioned media taken from TGFβ-stimulated ErbB2-expressing cells treated with doxycycline to achieve reduced ShcA levels was confirmed to contain increased levels of Chordin-like-1 compared with unstimulated controls. This same conditioned media was efficient at inhibiting the BMP-stimulated phosphorylation of Smad proteins 1/5/8 in ErbB2-expressing cells. Furthermore, this TGFβ upregulation of Chordin-like 1 production resulting from ShcA loss correlated with decreased activation of Smad1/5/8 in ShcA-deficient tumor cells in vivo, and may represent a transcriptional mechanism through which ShcA coordinates ErbB2 and TGFβ initiated tumor growth and invasion. Citation Format: Jason J. Northey, Zhifeng Dong, Chanele Cyr-Depauw, Sean Cory, Peter M. Siegel. ShcA is required for the TGFβ-induced repression of Chordin-like-1 in ErbB2-expressing breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A65.
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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) | 0.003 | 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".