Abstract 2747: Loss of S100A10 gene suppresses mammary tumor progression in PyMT mouse tumor model
Bibliographic record
Abstract
Abstract Introduction: S100A10 (p11) is a plasminogen receptor that we have shown is a master regulator of cellular plasmin generation by cancer cells and is also is essential and sufficient for macrophage migration to tumor sites. In the current study we have investigated the role of p11 in breast cancer tumor progression. Methods: We have employed gene profiling analysis of breast cancer patient tumors and an in depth study of the Polyoma Middle T (PyMT) transgenic mouse breast cancer model to interrogate the possible role of p11 in breast cancer. Results: Gene expression profiling from 176 primary breast cancer samples obtained through the CBCF tumor bank showed that p11 mRNA levels were significantly higher in tumors with high Ki67 immunoreactivity, was upregulated in high grade breast tumors, and was also significantly associated with poor patient prognosis (hazard ratio of 3.34). To further investigate the function of p11 in breast cancer, we established the MMTV-PyMT transgenic mouse mammary breast cancer model and generated two groups of animals – PyMT/p11-WT and PyMT/p11-null mice. We observed a significant delay in tumor onset and appearance of palpable tumours ias well as a dramatic reduction (5-fold at 20 weeks) in tumor growth in mice lacking p11 compared to WT controls. Importantly, the total tumor burden at the time of sacrifice was 3.5-fold lower for the p11-null mice concomitant with decreased tumour cell proliferation (Ki67), vascularity (CD31) and macrophage infiltration (F4/80). The histopathological progression to late carcinoma was delayed in PyMT/p11-null mice, with only 6% of PyMT/p11-null mice showing late carcinoma as compared to 69% PyMT/p11-WT at 20 weeks. Consistently, there was a 5-fold decrease in total metastatic foci in the lungs of the PyMT/p11-null mice. Experimental metastasis assay of p11-WT cells injected in p11-WT and p11-null mice showed a dramatic decrease in metastatic burden in p11-null mice suggesting a stromal involvement. Interestingly loss of p11 did not decrease plasmin generation in the PyMT tumors and cells obtained from tumors. Surprisingly, we also observed decreased plasmin independent migration and invasion with loss of p11. Conclusions: These studies suggest that p11 plays a critical role in breast tumor growth and metastasis, independent of its role as a plasminogen receptor. Future studies are aimed at elucidating the tumor cell or stroma specific role of p11 in breast cancer progression and identifying the intracellular function of p11 in this process. Citation Format: Alamelu Bharadwaj, Ryan Holloway, Patricia Colp, Rong-Zong Liu, Rosaline Godbout, Penny Barnes, Paola A. Marignani, David Waisman. Loss of S100A10 gene suppresses mammary tumor progression in PyMT mouse tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2747.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".