Bibliographic record
Abstract
The most frequent genomic alteration in breast cancer (BC) involves hemizygous loss of chromosome 16q (16q). This event occurs in up to 65% of cases. Interestingly, 16q includes two genes with recurrent mutations in BC: CDH1 and CBFB. CDH1 loss-of-function is one of the two most frequently identified focal mutations in lobular BC, along with gain-of-function mutations in PIK3CA. Here I report that homozygous deletion of mouse Cdh1 coupled with expression of activated Pik3ca induces lobular tumors. Based on transcriptional profiling and mass cytometry, these tumors showed immune suppression and exhaustion. This new model for immune-related invasive lobular carcinoma (IR-ILC) can be used as a platform to develop combination therapeutic regiments to improve outcomes for patients. Next, I tested for mammary tumor suppressor activity of Cbfb. To this end, I generated mice with homozygous deletion of Cbfb deletion together with a gain-of-function mutation in Pik3ca. As with Cdh1, homozygous loss of Cbfb dramatically increased the rate of mammary tumor formation. In most breast tumors with focal mutations in CDH1 or CBFB, the second allele is lost through homozygous deletion of 16q. Indeed, I refined both tumor models by crossing focal Cdh1 or Cbfb mutant alleles to mice with activated Pik3ca and to a novel mouse with loxP sites flanking a region of mouse chromosome 8 that is syntenic to 16q. The resulting mice developed mammary tumors that were histologically related to tumors in models for focal deletion of either tumor suppressor, thereby establishing a platform for discovery of therapeutics to treat 16q hemizygous BC. Interestingly, Cdh1 and Cbfb both showed haploinsufficient tumor suppressor activity when combined with activated Pik3ca suggesting that hemizygous loss of either gene may be at least partially responsible for section of 16q loss in BC. Finally, as 16q loss is so common, I tested for tumor formation in mice with mammary specific deletion of this region in the absence of other predisposing events. Remarkably, hemizygous loss of 16q-syntenic sequences was enough to initiate mammary tumor development. Thus, chromosome 16q is a locus for tumor suppression in BC.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 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".