Abstract 3905: Stem like cells in human breast cancer: EP4 as a therapeutic target
Bibliographic record
Abstract
Abstract Background: A tumor cell subset known as stem like cells (SLC) defy conventional therapies, requiring identification of SLC-specific therapeutic targets. We established that elevated COX-2 expression by breast cancer cells promotes tumor progression via inactivation of host immune cells, enhancement of cancer cell migration and invasiveness, and promotion of tumor-associated angiogenesis and lymphangiogenesis primarily by activation of the PGE-2 receptor EP4 on tumor and host cells. Cardiovascular side effects of long term use of COX-2 inhibitors argued for an alternative target, potentially EP4. Objectives/approaches: We asked whether COX-2 or EP4 additionally stimulates SLC in breast cancer. COX-2 and HER-2, often co-expressed in human breast cancer, are both major determinants of cancer progression. To define the roles of COX-2 in HER2 +ve and -ve cells, COX-2 cDNA was stably transfected into COX-2-low, HER-2-ve, ER+ve, non-metastatic MCF-7 and COX-2-ve, ER-ve, HER-2-high SKBR-3 human breast cancer cell lines to derive MCF-7-COX-2 and SKBR-3-COX-2 cells which were tested for changes in phenotype and functions in vitro and in vivo. Results: Both COX-2 over-expressing lines showed (1) EMT (low E-Cadherin and high Vimentin, Twist and N-Cadherin), (2) higher proliferation/ migration/ invasion, (3) upregulation of EP4 and angiogenic/ lymphangiogenic factors VEGF-A/C/D, (4) markedly increased SLC contents indicated by clonogenic spheroid formation for successive generations in vitro, increased ALDH activity and co-expression of COX-2 and multiple SLC markers in spheroids. (5) COX-2 expression markedly increased during spheroid formation in COX-2 disparate cell lines, indicating a selection of COX-2 expressing cells. (6) EP4 activation of COX-2 low cell lines with PGE2 or EP4 agonists markedly increased spheroid-forming efficiency. (7) Functional changes listed above (2-5) were blocked with COX-2 inhibitors or an EP4 antagonist (EP4A), indicating dependence on COX-2 and EP4 activity. (8) MCF-7-COX-2 cells showed dramatically increased lung colony forming ability and growth at 4-6 wks in NOD/SCID/GUSB null mice (identified by GUSB staining), which were blocked with EP4A treatment or EP4 knockdown; (9) MCF-7-COX-2 (as low as 5000) cells showed increased orthotopic tumorigenicity in NOD/SCID/IL-2Rγ deficient mice on transplantation for successive generations. (10) Finally, expression of COX-2 and EP4 were positively correlated with the SLC marker ALDH in human breast cancer tissues, and associated with poor patient survival. Conclusion/ Significance: EP4 represents a novel therapeutic target to eradicate SLCs in breast cancer. EP4 antagonists may spare cardiovascular side effects of COX-2 inhibitors, primarily attributed to cardio protective effects of PGI2. (Supported by the CBCF, Ontario Chapter and OICR grants to PKL, TBCRU and CIHR-STP fellowships to MM, CBCF fellowship to EL and a gift of EP4A, RQ-15986 by RaQualia Pharma). Citation Format: Mousumi Majumder, Xiping Xin, Ling Liu, Gillian Bell, Erin Landman, Mauricio Rodriguez- Torres, Lynne-Marie Postovit, David Hess, Peeyush K. Lala. Stem like cells in human breast cancer: EP4 as a therapeutic target. [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 3905. doi:10.1158/1538-7445.AM2014-3905
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.007 | 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".