Abstract P1-02-02: Processing of GPNMB by ADAM-10 in Breast Tumors Releases an Extracellular Domain with Angiogenic Properties
Bibliographic record
Abstract
Abstract Background: Glycoprotein non-metastatic B (GPNMB), also known as Osteoactivin, is a cell surface bound, transmembrane protein that is expressed in 41-74% of breast cancers. We have shown that it promotes migration, invasion and metastasis of breast cancer cells, that it is associated with shorter recurrence-free and overall survival times, and that it is most commonly expressed among breast tumors of the basal/triple-negative subtypes. Patients with basal/triple-negative breast cancer have aggressive disease and are not amenable to currently available targeted therapies. For these reasons GPNMB is an attractive target for therapeutic intervention in breast cancer; indeed, a GPNMB-targeted antibody-drug conjugate (CDX-011) has shown impressive clinical response among patients with GPNMB-positive breast cancer and is being investigated in Phase IIb clinical trials. Despite its promise as a therapeutic target in breast cancer, little is known about the functional role of GPNMB the primary tumor microenvironment. Materials and Methods: We have employed 66cl4 murine mammary carcinoma cells and human BT549 breast cancer cells to investigate the effects of GPNMB on tumor growth and angiogenesis, respectively in vivo. Control and GPNMB-expressing tumors were analyzed using immunohistochemistry for degree of proliferation apoptosis and angiogenesis. To better characterize functionally important domains of GPNMB we employed immunoblot and ELISA analyses to assess levels of full length, intact GPNMB and shed GPNMB ectodomain in breast cancer cells. Transient siRNA-mediated knockdown studies were used to identify sheddases responsible for GPNMB shedding. Finally, we employed in vitro migration assays to assess function of the shed extracellular domain (ECD) of GPNMB. Results: In this study we show that GPNMB promotes the outgrowth of mammary tumors in vivo and enhances their microvascular density. In an effort to investigate the functional domains of GPNMB that are responsible for this pro-angiogenic effect, we found that that the extracellular domain (ECD) of GPNMB is constitutively shed in breast cancer cells and show that this ECD is capable of inducing endothelial migration. Finally, we have implicated a disintegrin and metalloprotease-10 (ADAM10) as a novel sheddase responsible for liberation GPNMB ectodomain. Conclusion: In this study we have described ADAM10-mediated shedding of GPNMB ECD - a protein fragment that induces endothelial cell migration - as a novel mechanism by which GPNMB can promote angiogenesis in breast cancer. Further efforts to characterize the effect of GPNMB on endothelial cell function will be discussed. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-02-02.
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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".