Abstract 4053: Formin-binding protein-17 (FBP17) is a target of p53 and promotes invadopodia formation in breast cancer cells
Bibliographic record
Abstract
Abstract Invadopodia are extracellular matrix (ECM)-degrading structures that promote tissue invasion and metastasis of tumor cells. A family of adaptor proteins with F-BAR and SH3 domains, including FBP17 and Toca-1, have been identified as key scaffolds for recruiting actin regulatory proteins (eg. Cdc42, formins, N-WASP, dynamin) to promote formation of invadopodia in bladder and breast cancers, respectively. In this study, we investigated the potential role of FBP17 in breast cancer models. We observed FBP17 expression in normal breast epithelial cells (MCF10A), and at higher levels in basal breast cancer cell lines (MDA-MB-231) compared to luminal cell lines. Since basal breast cancers frequently harbor mutations in tumor suppressor p53, we tested whether wild-type (WT) p53 regulates expression of FBP17, which may explain higher expression in basal breast cancers. Camptothecin (CPT) treatment of WT p53-expressing breast cancer cells (MCF-7, DU4475) led to a dose dependent reduction in FBP17 mRNA and protein levels, and this was inversely correlated with p53 levels or its target p21WAF1. The downregulation of FBP17 was also observed using Nutlin-3, an Mdm2 inhibitor, indicating that WT p53 activation by multiple methods causes a rapid downregulation of FBP17. Currently we are testing whether this is a direct or indirect effect of p53 on FBP17 gene expression. As expected, FBP17 formed complexes with actin regulatory proteins (dynamin, cortactin, Arp2/3) that accumulate and promote invadopodia formation in MDA-MB-231 cells. Stable silencing of FBP17 in these cells led to a significant reduction in ECM degradation. This is consistent with FBP17 promoting invadopodia formation. Tumor xenograft models are in progress to determine whether FBP17 also promotes tumor metastasis. FBP17 expression levels in human breast tumors are currently being tested to determine whether altered expression occurs in molecular subtypes with frequent mutations in p53 (HER2, basal) and in their metastases. Overall, these results are consistent with FBP17 participating in cancer cell invasion, and supports further studies of its role in cancer metastasis. Citation Format: Harish Chander, Kathleen Watts, Justin Pogmore, Peter Truesdell, Colin Brien, Andrew W B Craig. Formin-binding protein-17 (FBP17) is a target of p53 and promotes invadopodia formation in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4053. doi:10.1158/1538-7445.AM2014-4053
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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".