Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer
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Kathryn E. Ware1,2, Jason A. Somarelli1,2, Daneen Schaeffer3, Jing Li4, Tian Zhang1,2, Sally Park2, Steven R. Patierno1,2, Jennifer Freedman1,2, Wen-Chi Foo8, Mariano A. Garcia-Blanco5,6, Andrew J. Armstrong1,2,7
1Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA
2Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
3Department of Oncology, Translational Research, Janssen Research and Development, Spring House, PA, USA
4Department of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA
5Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA
6Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA
7Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
8Department of Pathology, Duke University, Durham, NC, USA
Andrew J. Armstrong, email: Andrew.firstname.lastname@example.org
Kathryn E. Ware, email: email@example.com
Keywords: castration resistance, metastasis, enzalutamide, androgen receptor, Snail
Received: April 29, 2016 Accepted: June 20, 2016 Published: July 7, 2016
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.
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