Characterizing the disruption of tissue organization during early breast cancer development
Bibliographic record
Abstract
Breast cancer is a common disease affecting women worldwide, and although overall mortality is decreasing, incidence is increasing.The latter is partially due to better detection methods identifying lesions earlier, at pre-cancerous stages which are then resected.Since not all pre-cancerous lesions will progress to malignancy, I sought to better understand these earlier stages of breast cancer.Using human breast biopsy samples, as well as inducible the polyoma middle T (MIC) in vivo mouse model and organotypic cultures, I report in this thesis diverse mechanisms that contribute to loss of cell and tissue polarity in the development of carcinoma.We identified that a major mechanism observed in generating solid ducts involved progressive loss of cell polarity.This occurs through an initial increase in baseline proliferation rates, followed by altered cell division orientation.Next, the lumen collapses through reduced RhoA/myosin II activity at the apical membrane.Moreover, loss of tissue and cell polarity was reversible upon removal of oncogene stimulation.Furthermore, we found that depletion of Src tyrosine kinase in the MIC mouse model fails to produce mammary tumours.The mammary glands form enlarged ducts that fail to generate stratified epithelia by re-establishing proper mitotic spindle orientation, with no direct effect on proliferation.To examine if disrupted spindle orientation is necessary for tumour progression, we depleted the spindle orientation regulator LGN from the mammary epithelium.In normal tissue, LGN -/-glands resulted in randomized mitotic spindles, but was not sufficient to induce tumours or even disrupt tissue organization.However, LGN-deficient mammary glands unblocked tumour formation in MIC/Src -/-mice.This supports that spindle mis-orientation is a necessary and early step in breast cancer initiation.Together, these results demonstrate dynamic event of epithelial remodeling during the development of carcinoma, and reveal a previously unappreciated mechanism involving progressive polarity loss, manipulation of oriented cell division, and luminal collapse as key characteristics.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".