Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

dc.contributor.author

Ware, Kathryn E

dc.contributor.author

Somarelli, Jason A

dc.contributor.author

Schaeffer, Daneen

dc.contributor.author

Li, Jing

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Zhang, Tian

dc.contributor.author

Park, Sally

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Patierno, Steven R

dc.contributor.author

Freedman, Jennifer

dc.contributor.author

Foo, Wen-Chi

dc.contributor.author

Garcia-Blanco, Mariano A

dc.contributor.author

Armstrong, Andrew J

dc.coverage.spatial

United States

dc.date.accessioned

2017-08-01T13:30:40Z

dc.date.available

2017-08-01T13:30:40Z

dc.date.issued

2016-08-02

dc.description.abstract

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/27409172

dc.identifier

10476

dc.identifier.eissn

1949-2553

dc.identifier.uri

https://hdl.handle.net/10161/15123

dc.language

eng

dc.publisher

Impact Journals, LLC

dc.relation.ispartof

Oncotarget

dc.relation.isversionof

10.18632/oncotarget.10476

dc.subject

Snail

dc.subject

androgen receptor

dc.subject

castration resistance

dc.subject

enzalutamide

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metastasis

dc.title

Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

dc.type

Journal article

duke.contributor.orcid

Somarelli, Jason A|0000-0003-1510-9343

duke.contributor.orcid

Zhang, Tian|0000-0001-8914-3531

duke.contributor.orcid

Patierno, Steven R|0000-0003-0636-2128

duke.contributor.orcid

Armstrong, Andrew J|0000-0001-7012-1754

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/27409172

pubs.begin-page

50507

pubs.end-page

50521

pubs.issue

31

pubs.organisational-group

Basic Science Departments

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Clinical Science Departments

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Community and Family Medicine

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Duke

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Duke Cancer Institute

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Institutes and Centers

pubs.organisational-group

Medicine

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Medicine, Medical Oncology

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Molecular Genetics and Microbiology

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Pharmacology & Cancer Biology

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School of Medicine

pubs.organisational-group

Surgery

pubs.organisational-group

Surgery, Vascular Surgery

pubs.publication-status

Published

pubs.volume

7

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