TMPrSS2-ERG controls luminal epithelial lineage and antiandrogen sensitivity in PTEN and TP53-mutated prostate cancer

Alexandra M. Blee, Yundong He, Yinhui Yang, Zhenqing Ye, Yuqian Yan, Yunqian Pan, Tao Ma, Joseph Dugdale, Emily Kuehn, Manish Kohli, Rafael Jimenez, Yu Chen, Wanhai Xu, Liguo Wang, Haojie Huang

Research output: Contribution to journalArticle

13 Scopus citations

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–induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle–related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth. Conclusions: Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53–altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer.

Original languageEnglish (US)
Pages (from-to)4551-4565
Number of pages15
JournalClinical Cancer Research
Volume24
Issue number18
DOIs
StatePublished - Sep 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Blee, A. M., He, Y., Yang, Y., Ye, Z., Yan, Y., Pan, Y., Ma, T., Dugdale, J., Kuehn, E., Kohli, M., Jimenez, R., Chen, Y., Xu, W., Wang, L., & Huang, H. (2018). TMPrSS2-ERG controls luminal epithelial lineage and antiandrogen sensitivity in PTEN and TP53-mutated prostate cancer. Clinical Cancer Research, 24(18), 4551-4565. https://doi.org/10.1158/1078-0432.CCR-18-0653