TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Alexandra M BleeHaojie Huang

Abstract

Purpose: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance.Experimental Design: We generated a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten/Trp53 alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray.Results: Transgenic ERG expression in mice blocked Pten/Trp53 alteration-induce...Continue Reading

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Citations

Feb 27, 2019·International Journal of Cancer. Journal International Du Cancer·Mercedes Marín-AguileraBegoña Mellado
Mar 11, 2020·Nature Reviews. Clinical Oncology·Álvaro Quintanal-VillalongaCharles M Rudin
Jun 15, 2018·Asian Journal of Andrology·Alexandra M Blee, Haojie Huang
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Jul 24, 2020·The Journal of Clinical Investigation·Fei LiDong Gao
Feb 16, 2021·Frontiers in Oncology·Tongyue ZhangLimin Xia
Mar 7, 2021·International Journal of Molecular Sciences·Simona De SummaAmalia Azzariti
Jul 3, 2021·Cancers·Lauren K JillsonScott D Cramer
Aug 10, 2021·Lancet·Shahneen SandhuScott G Williams

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