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ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss
Open accessAbstract
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.
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“Driven by the biology of ETS transcription factor translocations in prostate cancer (Cancer Genome Atlas Research, 2015; Chen et al., 2013; Yu et al., 2010), we introduced the oncoprotein ERG into this system and demonstrated ERG is a bonafide AR cofactor, endowed with a LXXLL-like AR interacting motif (AIM) that can…”
BackgroundMethodInfluentialSelf-citationWasmuth, E. V., Hoover, E. A., Antar, A., Klinge, S., Chen, Y., & Sawyers, C. L. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922159117 · Cited by 50
Self-citationRapid interrogation of cancer cell of origin through CRISPR editing
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Self-citation
Metadata
- Authors
- Chen, Y., Chi, P., Rockowitz, S., Iaquinta, P. J., Shamu, T., Shukla, S., Gao, D., Sirota, I., Carver, B. S., Wongvipat, J., Scher, H. I., Zheng, D., & Sawyers, C. L.
- Venue
- Nature Medicine
- Published
- 2013-06-30
- Volume
- 19
- Issue
- 8
- Pages
- 1023-1029
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1986799557
- Cited by
- 282
- References
- 43
- FWCI
- 23.14
- Type
- journal article
- Language
- en
- Open access
- green
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