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, Robert Cardiff, J. L. Rocnik, Y. Yang, R. Pagliarini

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3815-3825
Number of pages11
JournalOncogene
Volume34
Issue number29
DOIs
StatePublished - Jul 21 2015

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Neuroendocrine Cells
Androgen Receptors
Cell Differentiation
Prostatic Neoplasms
Androgens
Genetic Translocation
Cell- and Tissue-Based Therapy
Transgenic Mice
Genes
Prostate
Cell Proliferation
Pharmacology
Phenotype
Gene Expression
Cell Line
Population
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Mounir, Z., Lin, F., Lin, V. G., Korn, J. M., Yu, Y., Valdez, R., ... Pagliarini, R. (2015). TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. Oncogene, 34(29), 3815-3825. https://doi.org/10.1038/onc.2014.308

TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. / Mounir, Z.; Lin, F.; Lin, V. G.; Korn, J. M.; Yu, Y.; Valdez, R.; Aina, O. H.; Buchwalter, G.; Jaffe, A. B.; Korpal, M.; Zhu, P.; Brown, M.; Cardiff, Robert; Rocnik, J. L.; Yang, Y.; Pagliarini, R.

In: Oncogene, Vol. 34, No. 29, 21.07.2015, p. 3815-3825.

Research output: Contribution to journalArticle

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, R, Rocnik, JL, Yang, Y & Pagliarini, R 2015, 'TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation', Oncogene, vol. 34, no. 29, pp. 3815-3825. https://doi.org/10.1038/onc.2014.308
Mounir, Z. ; Lin, F. ; Lin, V. G. ; Korn, J. M. ; Yu, Y. ; Valdez, R. ; Aina, O. H. ; Buchwalter, G. ; Jaffe, A. B. ; Korpal, M. ; Zhu, P. ; Brown, M. ; Cardiff, Robert ; Rocnik, J. L. ; Yang, Y. ; Pagliarini, R. / TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. In: Oncogene. 2015 ; Vol. 34, No. 29. pp. 3815-3825.
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AU - Brown, M.

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