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Tumor and Stem Cell Biology
Disrupting Androgen Receptor Signaling Induces Snail-Mediated Epithelial–Mesenchymal Plasticity in Prostate Cancer Lu Miao, Lin Yang, Rui Li, Daniel N. Rodrigues, Mateus Crespo, Jer-Tsong Hsieh, Wayne D. Tilley, Johann de Bono, Luke A. Selth, and Ganesh V. Raj DOI: 10.1158/0008-5472.CAN-16-2169 Article
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Published OnlineFirst May 22, 2017
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doi: 10.1158/0008-5472.CAN-16-2169
Abstract Epithelial-to-mesenchymal plasticity (EMP) has been linked to metastasis,
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stemness, and drug resistance. In prostate cancer, EMP has been
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associated with both suppression and activation of the androgen receptor
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(AR) signaling. Here we investigated the effect of the potent AR antagonist
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enzalutamide on EMP in multiple preclinical models of prostate cancer and
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patient tissues. Enzalutamide treatment significantly enhanced the expression of EMP drivers (ZEB1, ZEB2, Snail, Twist, and FOXC2) and
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mesenchymal markers (N-cadherin, fibronectin, and vimentin) in prostate
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cancer cells, enhanced prostate cancer cell migration, and induced prostate
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cancer transformation to a spindle, fibroblast-like morphology.
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Enzalutamide-induced EMP required concomitant suppression of AR
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signaling and activation of the EMP-promoting transcription factor Snail, as evidenced by both knockdown and overexpression studies. Supporting
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these findings, AR signaling and Snail expression were inversely correlated in C4-2 xenografts, patient-derived castration-resistant metastases, and clinical samples. For the first time, we elucidate a mechanism explaining the inverse relationship between AR and Snail. Specifically, we found that AR directly repressed SNAI1 gene expression by binding to specific ARresponsive elements within the SNAI1 promoter. Collectively, our findings demonstrate that de-repression of Snail and induction of EMP is an adaptive response to enzalutamide with implications for therapy resistance. Cancer Res; 77(11); 1–12. ©2017 AACR.
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Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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L. Miao and L. Yang are the co-first authors of this article.
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Received August 14, 2016.
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Revision received October 4, 2016. Accepted March 7, 2017.
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©2017 American Association for Cancer Research.
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Copyright © 2018 by the American Association for Cancer Research. Cancer Research Online ISSN: 1538-7445 Cancer Research Print ISSN: 0008-5472 Journal of Cancer Research ISSN: 0099-7013 American Journal of Cancer ISSN: 0099-7374
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