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

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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.

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Acknowledgements

We thank William R Sellers, Nicholas Keen, Frank Stegmeier and Wenlin Shao for helpful discussions; Cory Abate-Shen for helpful input; Alan Ho for FACS analysis; David Ruddy, Daniel Rakiec, Michael Morrissey, Kim Bellavance, Elina Pradhan, Christoph Lengauer, Markus Warmuth, Hui Gao, Peter Finan, Elvis Shehu, Chris Wilson, Peter Fekkes, Paola Capodieci, Myrtha Constant, Samuel Ho, Brant Firestone and Janet Sim for their input and contributions.

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Author notes

  1. M Korpal & P Zhu

    Present address: 5Current address: H3 Biomedicine, Cambridge, MA, USA.,

  2. J L Rocnik

    Present address: 6Current address: Sanofi, Cambridge, MA, USA.,

Authors and Affiliations

  1. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Z Mounir, F Lin, V G Lin, J M Korn, Y Yu, R Valdez, A B Jaffe, M Korpal, P Zhu, J L Rocnik, Y Yang & R Pagliarini

  2. Center for Comparative Medicine, University of California, Davis, CA, USA

    O H Aina & R D Cardiff

  3. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    G Buchwalter & M Brown

  4. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA

    G Buchwalter & M Brown

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  1. Z Mounir
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  2. F Lin
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Correspondence to R Pagliarini.

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Competing interests

ZM is the recipient of presidential postdoctoral fellowship from the Novartis Institutes for Biomedical Research. ZM, FL, VGL, JMK, YY, RV, ABJ, YY and RP are all employees of Novartis Institutes for Biomedical Research. MK and PZ are employees of H3 Biomedicine. MB is a consultant to Novartis and the recipient of sponsored research support from Novartis. JLR is an employee of Sanofi. The other authors declare no conflict of interest.

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Mounir, Z., Lin, F., Lin, V. et al. TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. Oncogene 34, 3815–3825 (2015). https://doi.org/10.1038/onc.2014.308

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