| Abstract: |
Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss. © 2013 Nature America, Inc. All rights reserved. |
| Keywords: |
signal transduction; controlled study; protein expression; dna-binding proteins; nonhuman; animal cell; mouse; phenotype; animals; mice; animal tissue; cell death; gene; mus; genes; animal experiment; animal model; inflammation; protein binding; cell line, tumor; angiogenesis; transcription factors; cell transformation, neoplastic; prostate cancer; prostatic neoplasms; prostate; transcription regulation; chromatin immunoprecipitation; nucleotide sequence; cancer cell; oncogene proteins; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; prostate epithelium; homozygote; cell migration; androgen receptor; upregulation; receptors, androgen; disease models, animal; transcriptome; histones; lysine; transcription factor ets; electroretinogram; transcription factor er81; principal component analysis; proto-oncogene proteins c-ets
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