Title | ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Li D, Zhan Y, Wang N, Tang F, Lee CJ, Bayshtok G, Moore AR, Wong EWP, Pachai MR, Xie Y, Sher J, Zhao JL, Khudoynazarova M, Gopalan A, Chan J, Khurana E, Shepherd P, Navone NM, Chi P, Chen Y |
Journal | Sci Adv |
Volume | 9 |
Issue | 14 |
Pagination | eadc9446 |
Date Published | 2023 Apr 05 |
ISSN | 2375-2548 |
Keywords | Animals, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Prostate, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Proto-Oncogene Proteins c-ets, Transcription Factors, Tumor Suppressor Protein p53 |
Abstract | The mechanisms underlying -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 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 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 overexpression alone, at sufficient dosage, can initiate prostate neoplasia. |
DOI | 10.1126/sciadv.adc9446 |
Alternate Journal | Sci Adv |
PubMed ID | 37018402 |
PubMed Central ID | PMC10075989 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States P50 CA092629 / CA / NCI NIH HHS / United States U01 CA224044 / CA / NCI NIH HHS / United States |