Either Kras Activation or Pten Loss Similarly Enhance the Mutant CTNNB1-Induced Genetic Program to Promote Granulosa Cell Tumor Development in Ovary and Testis.
Bibliographic record
Abstract
The stable activation of the WNT signaling effector beta-catenin (CTNNB1(ex3)) in ovarian granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life. Although loss of the tumor suppressor gene Pten alone rarely leads to GCTs, its disruption in granulosa cells that concomitantly express a dominant-stable CTNNB1 mutant accelerates tumor formation. Expression of mutant (oncogenic) KRASG12D in granulosa cells results in the arrest of proliferation, differentiation and apoptosis. In this study, we sought to determine if KRAS activation would retard or block the ovarian phenotype of mice expressing dominant-stable CTNNB1. Unexpectedly, transgenic mice bearing mutations of CTNNB1 and KRAS developed early-onset GCTs leading to premature death in a manner similar to the Ctnnb1;Pten mutant mice. GCT cells in these animals were characterized by increased rates of proliferation, decreased apoptosis and reduced expression of markers of granulosa cell differentiation relative to normal ovaries. Microarray and RT-PCR studies were performed comparing control ovaries, ovaries from mice expressing dominant-stable CTNNB1, and ovaries bearing early-stage tumors from mice with the CTNNB1 mutation and either Pten loss or KRAS activation. Results demonstrated that gene regulatory processes induced by CTNNB1 were mostly further enhanced by either KRAS activation or Pten loss, and that the latter mutations largely affected the expression of the same genes in remarkably similar patterns. Granulosa cells from the tumors proliferate in culture and retain expression of selected CTNNB1 target genes. In addition, concomitant activation of CTNNB1 and KRAS in Sertoli cells resulted in the development of granulosa cell tumors of the testis similar to those observed in the Ctnnb1;Pten mutant mice. Real time-PCR studies showed a partial overlap in gene regulatory processes associated with tumor development in the ovarian and testicular GCTs. Collectively, these results suggest that mutant stable CTNNB1 alters the granulosa cell genetic program and predisposes these cells to transformation whereby either KRAS activation or Pten loss induce GCT development from premalignant lesions via highly similar molecular mechanisms. Supported in part by NIH-HD-16229 and HD-07945 (J.S.R.) and the Canadian Institutes of Health Research (D.B.). (poster)
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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) | 0.000 | 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".