Abstract 788: Modeling tumor microenvironmental heterogeneity identifies CREBBP as a novel tumor suppressor in breast cancer
Bibliographic record
Abstract
Abstract Solid tumors display significant histological, genetic and micro-environmental intra-tumor heterogeneity that can change substantially over the course of their evolutionary trajectory. In particular, changes in the micro-environmental complexity within breast cancer such as hypoxic and nutrient deplete environments are associated with aggressive disease and a poor patient outcome. We sought to identify novel driver alterations in aggressive disease by employing a functional genomics screen in a 3-dimensional model of breast cancer progression that more accurately recapitulates in vivo micro-environmental heterogeneity. Screening of the top 200 recurrently mutated genes in breast cancer in cancer cell line spheroids identified several genes whose silencing impacted growth. A second targeted validation screen in a larger panel of triple negative cell line models showed that silencing of the histone acetyltransferase CREBBP, promoted growth in 3D but had limited effect under traditional 2D culture conditions. Investigation of TCGA and METABRIC datasets showed that CREBBP was more frequently mutated in triple negative breast cancers (TNBCs) and at least a third of TNBCs also displayed gene haploinsufficiency or complete loss of CREBBP. Interrogation of expression and proteomic datasets showed that loss of CREBBP resulted in the upregulation of the pro-proliferative transcription factor FOXM1. Significantly, this conserved FOXM1-driven transcriptional programme was also seen in multiple solid tumors with CREBBP alterations including lung, oesophageal, bladder and endometrial cancers. This was recapitulated in several CREBBP deficient cells where we identified that FOXM1 is driving altered metabolism, allowing cancer cells to grow under nutrient stress conditions. In summary, CREBBP is a bona fide tumor suppressor in up to a third of TNBCs, as well as a wide range of other solid tumors. CREBBP-altered tumors display up-regulation of FOXM1, which alters cancer cell metabolism under nutrient stress conditions. Moreover, CREBBP-altered tumors are selectively sensitive to small molecule inhibitors that target FOXM1 activity, suggesting that this maybe a viable targeted therapeutic approach for CREBBP altered cancers. Citation Format: Barrie Peck, Philip J. Bland, Patty T. Wai, Hannah Cottom, Sarah L. Maguire, Eamonn Morrison, Holly E. Barker, Divya Kriplani, Rebecca Marlow, Kalnisha Naidoo, Gareth Muirhead, Syed Haider, Frances Daley, Frederik Wallberg, Andrew N. Tutt, Rachael C. Natrajan. Modeling tumor microenvironmental heterogeneity identifies CREBBP as a novel tumor suppressor in breast cancer [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 788.
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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 | 0.000 | 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) | 0.001 | 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".