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

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Mounir Z,Lin F,Lin VG,Korn JM,Yu Y,Valdez R,Aina OH,Buchwalter G,Jaffe AB,Korpal M,Zhu P,Brown M,Cardiff RD,Rocnik JL,Yang Y,Pagliarini R

doi

10.1038/onc.2014.308

subject

Has Abstract

pub_date

2015-07-01 00:00:00

pages

3815-25

issue

29

eissn

0950-9232

issn

1476-5594

pii

onc2014308

journal_volume

34

pub_type

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