Abstract 21: p66ShcA is a contextual breast cancer metastasis promoter or suppressor depending on the tumor microenvironment
Bibliographic record
Abstract
Abstract Introduction: Src homology and collagen A (ShcA) adaptor proteins are essential during breast cancer progression. However, the role of the largest isoform, p66ShcA, is conflicting and still poorly understood. Under high levels of stress p66ShcA is phosphorylated on serine36, within its CH2 domain, allowing it to translocate to the mitochondria and induce the formation of reactive oxygen species (ROS) to promote apoptosis. Previously, we provided the first in vivo evidence that p66ShcA can influence both pro and anti-tumorigenic functions in ErbB2+ luminal breast cancer. Stable overexpression of p66ShcA reduced tumor outgrowth while simultaneously elevating the expression of mesenchymal genes to promote tumor plasticity. In this study, we evaluated the role of p66ShcA in metastatic dissemination to the lung in a model of basal breast cancer, which typically is associated with poor outcome. Hypothesis: p66ShcA regulates basal breast cancer metastasis to the lung. Methods: Screening a panel of basal breast cancer cells in vivo selected to the lung, liver and bone, we found p66ShcA enriched in lung and liver metastatic variant cell lines relative to parental breast cancer cells and those in vivo selected through the mammary fatpad. Using CRISPR/Cas technology we genetically deleted p66ShcA and rescued with p66ShcA-WT or a p66ShcA-S36A mutant. Lung metastatic basal breast cancer cells were injected into the fourth gland of the mammary fatpad. Tumors were measured using calipers 3 times/week following first palpation (>50mm3) followed by surgical resection to monitor the lung metastatic burden. In addition, we performed tail vein injections to monitor lung metastatic burden following direct entry into the circulation. Results: Loss of p66ShcA significantly reduced the metastatic burden to the lung following surgical tumor resection and this reduction was partially rescued by stable overexpression of wild type (WT), but not S36A mutated p66ShcA from the primary site. These effects were not due to altered anti-oxidant expression levels, changes in oxidative DNA Damage or microvessel density. Intriguingly, we found that WT-rescue of p66ShcA significantly elevated the migratory speed of breast cancer cells in vitro and corroborates our in vivo metastatic burden data. However, this is in stark contrast to our tail vein data, where WT-rescue of p66ShcA significantly inhibited lung metastasis. Conclusion: p66ShcA is required for efficient metastasis to the lung in a mitrochondrial-ROS-dependent fashion from the primary site. Our data suggest that cues from the tumor microenvironement of the mammary fatpad are essential for successful colonization and outgrowth at oxygen rich sites, such as the lung, as breast cancer cells with elevated expression of p66ShcA directly entering the circulation suppressed lung metastatic burden. Citation Format: Jesse Hudson, Kyle Lewis, Julien Senécal, Alexander Kiepas, Sébastien Tabariès, Valérie Sabourin, Ryuhjin Ahn, Rachel La Selva, Peter Siegel, Giuseppina Ursini-Siegel. p66ShcA is a contextual breast cancer metastasis promoter or suppressor depending on the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 21.
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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) | 0.007 | 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".