Abstract 5311: Transducer of Cdc42-dependent actin assembly-1 (Toca-1) promotes breast cancer invasion and metastasis
Bibliographic record
Abstract
Abstract Metastatic breast adenocarcinomas display activation signatures for signaling pathways like Epidermal Growth Factor Receptor (EGFR) that trigger cell motility and tissue invasion. Transducer of Cdc42-dependent actin assembly-1 (Toca-1) is an adaptor protein that promotes recruitment of actin nucleation promoting factors to cellular membranes. Although these actin regulatory proteins have been linked to breast cancer invasion, the role of Toca-1 in this process has not been reported. In this study, breast cancer cell lines with a range of invasive and metastatic properties were used, including human MDA-MB-231 cells, rat MTLn3 cells, and MTLn3-B1 cells expressing human EGFR. To test the role of Toca-1 in these cell lines, we established stable Toca-1 knock-down (KD) using lentiviral delivery of shRNAs specific for human or rat Toca-1. Here, we report that Toca-1 is expressed in highly invasive breast cancers cell lines, and that Toca-1 co-localizes with components of invadopodia. Toca-1 localizes to the filamentous actin-rich core of invadopodial protrusions in breast cancer cells that are actively degrading the extracellular matrix (ECM). In MDA-MB-231 cells, Toca-1 KD led to a significant defect in EGF-induced cell migration and invasion compared to control cells. This correlated with a significant defect in EGF- and Src-induced ECM digestion in Toca-1 KD compared to control MDA-MB-231 cells. Next, control and Toca-1 KD cells were compared in orthotopic mammary tumors that were xenografted in Rag2−/−:[[Unsupported Character - Symbol Font ]]c−/− mice. Although Toca-1 KD remained effective in primary tumors, no defects in tumor growth were observed. However, mice bearing Toca-1 KD cell tumors displayed a significant reduction in spontaneous metastases to the lung. Similar results were obtained for weakly metastatic MDA-MB-231 cells and highly metastatic MTLn3-B1 cells. In contrast, Toca-1 was not required for efficient lung seeding following tail vein injection of MTLn3-B1 cells, suggesting that Toca-1 functions at an early step in the dissemination of metastatic breast tumor cells. Taken together, this investigation identifies Toca-1 as a pro-invasive protein in breast cancer, and a potential therapeutic target to limit tumor metastasis. 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 5311. doi:1538-7445.AM2012-5311
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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) | 0.004 | 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".