Abstract 5217: The role of miR-526b in COX-2 mediated breast cancer progression via EP4 signaling
Bibliographic record
Abstract
Abstract A minor tumour cell subset, known as stem-like cells (SLCs), appears to defy conventional therapy, causing relapse. Thus, identification of SLC-specific therapeutic targets and markers is urgently needed. Our laboratory has established that aberrant expression of COX-2 promotes breast cancer progression via multiple mechanisms including SLC induction owing to activation of the PGE receptor EP4 which signals via the canonical cAMP/PKA, and non-canonical PI3K-AKT pathways. Differential gene and microRNA (miR) expression micro arrays in human breast cancer cell lines stably transfected to over-express COX-2 revealed up-regulation of miR-526b. We sought to determine if miR-526b is induced by EP4 activation and whether it promotes breast cancer progression, including SLC stimulation. COX-2-ve human breast cancer cell lines MCF-7 (ER+, HER-2-) and SKBR-3 (ER-, HER-2+) were stably transfected to over-express miR-526b (MCF7-526b and SKBR3-526b), and functional assays were performed. The cells exhibited enhanced proliferation, migration and invasiveness, and increased tumoursphere-forming efficiency on ultra-low attachment plates (in vitro surrogate of SLC phenotype), compared to empty vector-transfected and parental controls. These results indicate that miR-526b is a COX-2 induced oncogenic microRNA. In order to assess the roles of miR-526b in vivo, MCF7-526b, SKBR3-526b, or empty vector control cells were injected into the tail vein of NOD/SCID/GUSB-null female mice. Both miR-526b over-expressing cell lines revealed a significantly increased ability to form proliferative lung colonies at 4 weeks identified with HLA staining and EdU proliferation marker. To examine the role of EP4 activation in miR-526b up-regulation, MCF-7 cells cultured as monolayers or tumourspheres were treated with PGE2 or an EP4 agonist, PGE1OH. Both ligands induced a significant over-expression of miR-526b in both culture conditions. Conversely, MCF7-COX-2 cells treated with either an EP4 specific antagonist (ONO-AE3-208) or a COX-2 inhibitor (NS-398) displayed significant reduction in miR-526b expression, as quantified with qPCR. To investigate the role of PI3K-AKT pathway of EP4 signaling in miR-526b expression, PI3K was stimulated with PGE2 or PGE1OH in MCF7 cells, and inhibited with LY294002 or Wortmannin in MCF7-COX-2 cells. MiR-526b expression levels quantified with qPCR revealed significant increases and declines, respectively, with PI3K-AKT pathway stimulators and inhibitors applied to the above cell lines. Together these results suggest an important association of miR-526b with EP4-induced SLC stimulation and breast cancer progression, and the possibility that miR-526b may be used as a biomarker for monitoring patients and personalizing therapy. (Supported by the CBCF, Ontario chapter and the OICR funds to PKL. EL holds a CBCF and CIHR-STP Graduate Fellowship and MM a TBCRU and CIHR-STP Post Doctoral fellowship). Citation Format: Erin O. Landman, Mousumi Majumder, Ling Liu, Peeyush K. Lala. The role of miR-526b in COX-2 mediated breast cancer progression via EP4 signaling. [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 5217. doi:10.1158/1538-7445.AM2014-5217
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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) | 0.004 | 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".