TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation

Z Mounir; F Lin; V G Lin; J M Korn; Y Yu; R Valdez; O H Aina; G Buchwalter; A B Jaffe; M Korpal; P Zhu; M Brown; R D Cardiff; J L Rocnik; Y Yang; R Pagliarini

doi:10.1038/onc.2014.308

TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation

Oncogene. 2015 Jul;34(29):3815-25. doi: 10.1038/onc.2014.308. Epub 2014 Sep 29.

Authors

Z Mounir¹, F Lin¹, V G Lin¹, J M Korn¹, Y Yu¹, R Valdez¹, O H Aina², G Buchwalter³, A B Jaffe¹, M Korpal¹, P Zhu¹, M Brown³, R D Cardiff², J L Rocnik¹, Y Yang¹, R Pagliarini¹

Affiliations

¹ Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
² Center for Comparative Medicine, University of California, Davis, CA, USA.
³ 1] Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA [2] Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

PMID: 25263440
DOI: 10.1038/onc.2014.308

Abstract

The biological outcome of TMPRSS2:ERG chromosomal translocations in prostate cancer (PC) remains poorly understood. To address this, we compared the transcriptional effects of TMPRSS2:ERG expression in a transgenic mouse model with those of ERG knockdown in a TMPRSS2:ERG-positive PC cell line. This reveals that ERG represses the expression of a previously unreported set of androgen receptor (AR)-independent neuronal genes that are indicative of neuroendocrine (NE) cell differentiation-in addition to previously reported AR-regulated luminal genes. Cell sorting and proliferation assays performed after sustained ERG knockdown indicate that ERG drives proliferation and blocks the differentiation of prostate cells to both NE and luminal cell types. Inhibition of ERG expression in TMPRSS2:ERG-positive PC cells through blockade of AR signaling is tracked with increased NE gene expression. We also provide evidence that these NE cells are resistant to pharmacological AR inhibition and can revert to the phenotype of parental cells upon restoration of AR/ERG signaling. Our findings highlight an ERG-regulated mechanism capable of repopulating the parent tumor through the transient generation of an anti-androgen therapy-resistant cell population, suggesting that ERG may have a direct role in preventing resistance to anti-androgen therapy.

MeSH terms

Animals
Antibiotics, Antineoplastic / pharmacology
Benzamides
Cell Differentiation / drug effects
Cell Differentiation / genetics*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / genetics*
Disease Models, Animal
Doxorubicin / pharmacology
Epithelial Cells / metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Male
Mice, Transgenic
Microscopy, Confocal
Neuroendocrine Cells / metabolism
Nitriles
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism
Phenylthiohydantoin / analogs & derivatives
Phenylthiohydantoin / pharmacology
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
RNA Interference
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Serine Endopeptidases / genetics*
Serine Endopeptidases / metabolism
Trans-Activators / genetics*
Trans-Activators / metabolism
Transcriptional Regulator ERG
Translocation, Genetic

Substances

Antibiotics, Antineoplastic
Benzamides
ERG protein, human
Nitriles
Oncogene Proteins, Fusion
Receptors, Androgen
Trans-Activators
Transcriptional Regulator ERG
Phenylthiohydantoin
Doxorubicin
enzalutamide
Serine Endopeptidases
TMPRSS2 protein, human

Associated data

GEO/GSE60771
GEO/GSE61008