| First Author | Li D | Year | 2023 |
| Journal | Sci Adv | Volume | 9 |
| Issue | 14 | Pages | eadc9446 |
| PubMed ID | 37018402 | Mgi Jnum | J:334551 |
| Mgi Id | MGI:7460800 | Doi | 10.1126/sciadv.adc9446 |
| Citation | Li D, et al. (2023) ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer. Sci Adv 9(14):eadc9446 |
| abstractText | The mechanisms underlying ETS-driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse with prostate-specific expression of the ETS factor, ETV4, at lower and higher protein dosage through mutation of its degron. Lower-level expression of ETV4 caused mild luminal cell expansion without histologic abnormalities, and higher-level expression of stabilized ETV4 caused prostatic intraepithelial neoplasia (mPIN) with 100% penetrance within 1 week. Tumor progression was limited by p53-mediated senescence and Trp53 deletion cooperated with stabilized ETV4. The neoplastic cells expressed differentiation markers such as Nkx3.1 recapitulating luminal gene expression features of untreated human prostate cancer. Single-cell and bulk RNA sequencing showed that stabilized ETV4 induced a previously unidentified luminal-derived expression cluster with signatures of cell cycle, senescence, and epithelial-to-mesenchymal transition. These data suggest that ETS overexpression alone, at sufficient dosage, can initiate prostate neoplasia. |
