Abstract A037: YB-1 transforms mammary epithelial cells through chromatin remodeling leading to the development of basal-like breast cancer
Bibliographic record
Abstract
Abstract There is growing evidence that cancer-initiation could result from epigenetic changes. Y-box binding protein-1 (YB-1) is a transcription/translation factor that promotes the formation of tumors in transgenic mice; however, the early molecular events leading up to this are not understood. To address this in a human model system, YB-1 was expressed in mammary epithelial cells under a tetracycline-inducible promoter. The induction of YB-1 drove the development of ductal carcinoma in situ (DCIS) in vitro. Underlying these events, YB-1 induced p300, promoted its nuclear localization, and heightened histone acetylation leading to chromatin relaxation. Subsequently, chromatin relaxation allowed YB-1 to bind to the BMI1 promoter based on chromatin immunoprecipitation. The induction of BMI1 engaged the PRC1 complex as histone H2A was ubiquitinated and p16INK4a was silenced. These events manifested functionally in sustained self-renewal that occurred in a BMI1 dependent manner. Conversely, p300 inhibition with anacardic acid prevented YB-1 from binding to the BMI1 promoter and thereby subverted self-renewal. Accordingly, transient expression of YB-1 in the normal mammary 184hTERT and MCF10A cells had the same effect on chromatin remodeling and self-renewal. Despite these early changes, full malignant transformation was not achieved until RSK2 was expressed leading to elevated hTERT activity. The YB-1/RSK2/hTERT expressing cells formed DCIS and invasive ductal carcinoma in mice that were molecularly subtyped as basal-like breast cancer (BLBC). We conclude that YB-1 cooperates with p300 to allow BMI1 to over-ride p16INK4a enabling self-renewal and the formation of tumors. Citation Format: Alastair H. Davies, Kristen M. Reipas, Natalie Firmino, Anna L. Stratford, Rachel Berns, Abbas Fotovati, Mary Pambid, Kaiji Hu, Chris Maxwell, Gordon B. Mills, Sandra E. Dunn. YB-1 transforms mammary epithelial cells through chromatin remodeling leading to the development of basal-like breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A037.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".