Project description:We performed expression mouse profiling of prostates of 3 month WT, ERG, PTEN f/f and Pten f/f;ERG mice. For WT and ERG prostates, entire prostates were dissected and total RNA immediated harvested. For Pten f/f and Pten f/f;ERG prostates, the Ventral Lobe was dissected.
Project description:Translocation of ETS transcription factors including ERG and ETV1 occur in half of all prostate cancers. We generated a mouse model of ERG ovexpression (Rosa26-ERG) which when crossed into prostate specific probasin-Cre, expressed ERG specifically in the prostate. We crossed Rosa26-ERG into Pten flox/flox allele to generate compound GEMM mouse. Here, we determined the genomic binding sites of ERG, AR, and the histone marks H3K4me1 and H3K4me3 that maps enhancers and promoters respectively in the prostates of these mice.
Project description:Translocation of ETS transcription factors including ERG and ETV1 occur in half of all prostate cancers. We generated a mouse model of ERG ovexpression (Rosa26-ERG) which when crossed into prostate specific probasin-Cre, expressed ERG specifically in the prostate. We crossed Rosa26-ERG into Pten flox/flox allele to generate compound GEMM mouse. Here, we determined the genomic binding sites of ERG, AR, and the histone marks H3K4me1 and H3K4me3 that maps enhancers and promoters respectively in the prostates of these mice. The prostate of four six month old mice of each genotype were pooled. The chromatin was isolated and ChIP-Seq performed.
Project description:We performed expression mouse profiling of prostates of 3 month WT, ERG, PTEN f/f and Pten f/f;ERG mice. For WT and ERG prostates, entire prostates were dissected and total RNA immediated harvested. For Pten f/f and Pten f/f;ERG prostates, the Ventral Lobe was dissected. Mice are in the C57B6 background. The prostate were harvested and RNA isolated by standard protocols and analyzed by expression profiling.
Project description:We performed expression mouse profiling of prostates of 3 month PTEN f/f and Pten f/f;R26(ERG) mice and assessed the response to 3 days of castration.
Project description:We performed expression mouse profiling of prostates of 3 month PTEN f/f and Pten f/f;R26(ERG) mice and assessed the response to 3 days of castration. Mice are in the C57B6 background. Two mice in each group were castrated. Three days after castration, the prostate were harvested and RNA isolated by standard protocols and analyzed by expression profiling.
Project description:The current study defines the how ERG, PTEN, and AR inteact to regulate the transciptome in established prostate cancers. Prostate cancer organoids were derived from established prostate cancer in GEM models harboring ERG over-expression and/or loss of PTEN and cultured in vitro using prostate epithelial organoid culture conditions. The established organoids were then isolated as individual clones in triplicate and CRISPR strategies were employeed to knock out ERG and AR. RNA was isolated under physiologic steady state growth conditions and 24 hour treatment with the AR inhbitor MDV3100 in a subset of ERG-PTEN CRISPR ERG organoids.
Project description:Lineage plasticity is a major mechanism driving prostate cancer progression and antiandrogen therapy resistance. Deletions or mutations in phosphatase and tensin homolog (PTEN) and TP53 tumor suppressor genes have been linked to lineage plasticity in prostate cancer. Fusion-driven overexpression of the E-twenty-six transformation specific (ETS)-related gene (ERG), encoding an oncogenic transcription factor, is observed in approximately 50% of all prostate cancers, yet its role in prostate cell lineage determination remains elusive. Here we demonstrate that transgenic expression of prostate cancer-associated ERG blocks Pten and Trp53 mutation-induced decreased expression of Ar and its downstream target genes and loss of luminal epithelial cell identity in the mouse prostate. Integrative analyses of ERG chromatin-immunoprecipitation sequencing (ChIP-seq) and transcriptome data show that ERG suppresses expression of a subset of cell cycle-promoting genes and RB phosphorylation, which in turn causes repression of E2F1-mediated expression of non-epithelial lineage genes. Xenograft studies show that PTEN/TP53 double mutated prostate tumors are responsive to the cyclin-dependent kinase 4 or 6 (CDK4/6) inhibitor palbociclib, but resistant to the AR inhibitor enzalutamide, while ERG/PTEN/TP53 triple-mutated prostate tumors behave completely opposite. Our studies identify ERG and the repressed cell cycle gene signature as intrinsic inhibitors of PTEN/TP53 double mutation-elicited lineage plasticity in prostate cancer. Our findings also suggest that ERG fusion can be utilized as a biomarker to guide the treatment of PTEN/TP53-mutated, RB1-intact prostate cancer with either antiandrogen or anti-CDK4/6 therapies.
Project description:The current study defines the how ERG, PTEN, and AR inteact to regulate the transciptome in established prostate cancers. Prostate cancer organoids were derived from established prostate cancer in GEM models harboring ERG over-expression and/or loss of PTEN and cultured in vitro using prostate epithelial organoid culture conditions. The established organoids were then isolated as individual clones in triplicate and CRISPR strategies were employeed to knock out ERG and AR. ChIP seq was performed under standard growth and media conditions.
