ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer Journal Article
| Authors: | Li, D.; Zhan, Y.; Wang, N.; Tang, F.; Lee, C. J.; Bayshtok, G.; Moore, A. R.; Wong, E. W. P.; Pachai, M. R.; Xie, Y.; Sher, J.; Zhao, J. L.; Khudoynazarova, M.; Gopalan, A.; Chan, J.; Khurana, E.; Shepherd, P.; Navone, N. M.; Chi, P.; Chen, Y. |
| Article Title: | ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer |
| Abstract: | 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. |
| Keywords: | genetics; mouse; animal; metabolism; animals; mice; transcription factor; pathology; protein p53; transcription factors; cell transformation, neoplastic; prostatic neoplasms; gene expression regulation; gene expression regulation, neoplastic; prostate; cell transformation; prostate tumor; tumor suppressor protein p53; prostatic intraepithelial neoplasia; transcription factor ets; proto-oncogene proteins c-ets; humans; human; male; etv4 protein, human |
| Journal Title: | Science Advances |
| Volume: | 9 |
| Issue: | 14 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2023-04-07 |
| Start Page: | eadc9446 |
| Language: | English |
| DOI: | 10.1126/sciadv.adc9446 |
| PUBMED: | 37018402 |
| PROVIDER: | scopus |
| PMCID: | PMC10075989 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding authors are Ping Chi and Yu Chen -- Export Date: 1 May 2023 -- Source: Scopus |
