Abstract 2712: Identification of tumor initiating genes RPL39 and MLF2 that mediate lung metastasis through nitric oxide signaling and mesenchymal to epithelial transition.
Bibliographic record
Abstract
Abstract Triple negative breast cancer (TNBC) is the most aggressive and lethal form of cancer characterized by lack of estrogen, progesterone and Her2 receptors. It is prevalent in women of African American descent, often present in younger and premenopausal women. It shows high risk of recurrence and frequently metastasizes to lungs and brain, resulting in poor overall prognosis. There is no targeted therapy for TNBC as it does not respond to hormonal therapy and is intrinsically resistance to conventional chemotherapy. It is therefore imperative to understand the mechanism of survival of these cancers and unravel its biological pathways and modes of progression. We have previously described breast cancer stem cells (BCSC) to be intrinsically resistant to treatment which is further confirmed by recent publications by other groups that describe direct functional evidence for the same. Using genomic assays, we traced a BCSC gene signature comprising of 477 genes derived from patient biopsies. On selective shRNA knockdown of these genes we identified RPL39 and MLF2 as the top two candidates that affect BCSC self-renewal. Selective siRNA knockdown of RPL39 and MLF2 in human cancer xenografts, showed reduced tumor volume and lung metastases with a concomitant decrease in BCSC markers. Thus, targeting BCSCs in combination with chemotherapy should eliminate the heterogeneous populations within a tumor. Additionally, next generation RNA-seq confirmed mutations in RPL39 and MLF2 in 50% of lung metastases from breast cancer patients. In vitro and in vivo siRNA knockdown of RPL39 and MLF2 showed decrease in nitric oxide synthase, suggesting that these genes are driven by nitric oxide signaling. In conclusion this study reveals novel tumor initiating genes, RPL39 and MLF2 that target the breast cancer stem cells and also show impact on lung metastasis. Our findings enhance the understanding of treatment resistant breast cancer stem cells, the mutations that cause metastases and also lay foundation for developing new therapies for such cancers with poor prognosis. Citation Format: Bhuvanesh Dave, Sergio Granados, Junhua Mai, Dong Soon Choi, Ding Cheng Gao, Sucharita Mitra, Haifa Shen, Senthil Muthuswamy, Vivek Mittal, Mauro Ferrari, Jenny Chang. Identification of tumor initiating genes RPL39 and MLF2 that mediate lung metastasis through nitric oxide signaling and mesenchymal to epithelial transition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2712. doi:10.1158/1538-7445.AM2013-2712
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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) | 0.003 | 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".