Distinct mouse chromosome 11 (human 17q) amplifications develop in mouse breast tumors induced by oncogenic ERBB2 or polyoma virus middle T antigen
Bibliographic record
Abstract
1904 We investigated mouse breast tumors induced by expression of oncogenic ERBB2 or PyMT using array comparative genomic hybridization (array CGH) to identify recurrent genome copy number aberrations and reveal cooperative secondary mutational events. We assessed 3 models in this study: 1) TM - contains an activated form of Erbb2 (Neu-NT) knocked into the endogenous mouse Erbb2 locus, 2) MT - expresses PyMT under control of the mouse mammary tumor virus (MMTV) promoter, 3) DB - expresses a mutant variant of PyMT (Y315/322F) unable to activate PI3K, also under control of the MMTV promoter. Our studies using low resolution genome scanning arrays revealed the presence of high level chromosome 11 amplifications in the TM and DB models. This region is syntenic with human 17q21-25, a recurrently gained/amplified locus in human breast cancer. To investigate this locus further, we developed DNA microarrays containing a contig of BAC clones spanning the distal 30Mb of mouse chromosome 11, encompassing the ERBB2 oncogene. Assessment of TM, MT, and DB tumors revealed that the amplifications in the TM and DB models that were spatially distinct. A total of 17/20 TM tumors showed recurrent amplifications of the ERBB2 locus, which generally involved a single peak and encodes multiple genes. We defined a minimal 280kb common amplicon, nearly identical to that observed in human tumors. The conserved amplicon structure in mouse and human breast tumors suggests that multiple genes are co-selected and act in concert to drive tumor formation. In the Db model we observed high level amplifications in 8/16 tumors, ∼15-20Mb distal to the ERBB2 amplicon in TM tumors. Unlike the structured ERBB2 amplicon in the TM model, the Db amplicons were more genomically complex, often containing multiple peaks. These high level amplifications were not observed in Db hyperplasias (n=6) suggesting that they are involved in the hyperplastic to tumor switch in this model. Further, high level amplifications were not observed in PyMT induced tumors, suggesting that the amplified genes play a role in restoring important tumorigenic pathways (e.g. PI3K) and phenotypes (e.g. suppressed apoptosis) inactivated due to the Y315/322F mutation. To determine whether amplification results in over expression we quantitatively assessed mRNA expression levels of amplified genes Grb2 and Itgb4 relative to Gus using Taqman and correlated expression with genome copy number. Both genes showed strong correlations with Grb2 and Itgb4 respectively showing Pearson’s correlations of 0.86 and 0.72. Our results set the stage for detailed studies aimed at characterization of genes mapping to 17q21-25 (mouse chromosome 11) that are functionally important for breast tumor formation.
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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 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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 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".