Abstract 2260: Defining molecular mechanisms linking Endophilin A2 to metastasis in human breast cancer models
Bibliographic record
Abstract
Abstract Breast cancers in the human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC) subtypes have high rates of tumor metastasis. Tumor metastasis is driven by formation of invadopodia that degrade extracellular matrix (ECM) in basement membranes to spread locally and colonize distant sites. Endophilin A2 (Endo II) is an adaptor protein that coordinates internalization and trafficking of receptors that drive invadopodia formation and breast cancer metastasis. We have recently identified Endo II as a positive regulator of human TNBC metastasis, invadopodia formation, epidermal growth factor receptor (EGFR) internalization and signaling. Here, we extend these studies of Endo II to HER2 breast cancers, and define molecular mechanisms that link Endo II to invadopodia formation and cell invasion. Analysis of Endo II expression in human invasive ductal carcinomas revealed significantly high expression of Endo II in HER2 primary tumors, and significantly higher expression in paired lymph node metastases compared to other subtypes. We also observed that high levels of Endo II mRNA was associated with reduced rates of relapse free survival in patients with lymph node positive, estrogen receptor negative tumors. This correlates with our findings that Endo II promotes invadopodia formation and breast cancer cell invasion. Mechanistically, these defects may be due to reduced EGFR signaling and lowered expression of epithelial-mesenchymal transition (EMT) signature genes observed in Endo II knock-down (KD) cells. We are currently validating these results in mammary orthotopic tumor xenograft models of HER2 and TNBC cell models with stable Endo II KD. Together, these findings identify high levels of Endo II in high risk breast cancer subtypes, with high expression of EMT genes, and a potential link between Endo II levels and poor prognosis in breast cancer patients. Citation Format: Tomas Baldassarre, Kathleen Watt, Peter Truesdell, Mark Schneider, Sandip Sengupta, Andrew WB Craig. Defining molecular mechanisms linking Endophilin A2 to metastasis in human breast cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2260. doi:10.1158/1538-7445.AM2015-2260
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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 | 0.002 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".