title: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Mounir
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Lin
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: V G
authors.initials: VG
authors.lastname: Lin
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Korn
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Valdez
authors.affiliation: Center for Comparative Medicine, University of California, Davis, CA, USA.
authors.forename: O H
authors.initials: OH
authors.lastname: Aina
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Buchwalter
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Jaffe
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Korpal
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Brown
authors.affiliation: Center for Comparative Medicine, University of California, Davis, CA, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Cardiff
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Rocnik
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pagliarini
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D055099:Neuroendocrine Cells / Q000378:metabolism; D009570:Nitriles; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D014178:Translocation, Genetic
chemical_list: D000903:Antibiotics, Antineoplastic; D001549:Benzamides; C072312:ERG protein, human; D009570:Nitriles; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D010669:Phenylthiohydantoin; D004317:Doxorubicin; C540278:enzalutamide; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human