The role of GPNMB in breast tumor progression
Bibliographic record
Abstract
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer related deaths among Canadian women. Development of distant metastases is the leading cause of morbidity and mortality from this disease. Breast cancer is a highly heterogeneous disease that is amenable to intervention with targeted therapeutics; however, therapies that are currently available have limited efficacy in the metastatic setting. To identify novel molecular mediators of breast cancer bone metastasis that might also serve as therapeutic targets, we subjected 4T1 mammary carcinoma cells to in vivo selection in Balb/c mice and isolated sub-populations with an aggressively bone-metastatic phenotype. Gene expression profiling of these cells revealed Glycoprotein NMB (GPNMB), also known as Osteoactivin, as a gene that was highly expressed in bone metastatic breast cancer cells. GPNMB is a type I transmembrane, cell surface expressed protein with an extracellular RGD and PKD domains and a cytoplasmic hemITAM signaling motif that had not previously been implicated in breast cancer. We demonstrate that ectopic GPNMB expression was sufficient to promote migration and invasion of breast cancer cells in vitro and the formation of bone metastases in vivo.Subsequently, we analyzed GPNMB mRNA and protein expression levels in hundreds of breast tumors and found that GPNMB expression positively correlates with increased risk of metastasis and shorter overall survival times. We have also demonstrated that GPNMB is most commonly expressed in breast tumors belonging to the triple negative subtype, for which there are no targeted therapies currently available. We showed for the first time that CDX-011, a GPNMB-targeted monoclonal antibody-drug conjugate, was capable of killing GPNMB-expressing breast cancer cells in vitro and inducing tumor regression in vivo. Finally, we investigated the effects of GPNMB on primary tumor progression and found that it inhibits tumor cell apoptosis while enhancing angiogenesis and tumor growth in vivo. We demonstrate that the extracellular domain (ECD) of GPNMB can be proteolytically cleaved and shed from the surface of breast cancer cells, which is mediated by ADAM10. We postulated that the shed extracellular domain (ECD) of GPNMB might be responsible for some of its pro-angiogenic effects and showed that this ECD was indeed capable of inducing endothelial cell migration in vitro.The body of work described in this thesis is the first to identify GPNMB as a functional mediator of breast cancer growth and metastasis and to validate it as an important clinical target in human breast cancer.
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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 | 0.000 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".