title: Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.
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.
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.|Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Ware
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.|Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Somarelli
authors.affiliation: Department of Oncology, Translational Research, Janssen Research and Development, Spring House, PA, USA.
authors.forename: Daneen
authors.initials: D
authors.lastname: Schaeffer
authors.affiliation: Department of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.|Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.|Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Patierno
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.|Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Freedman
authors.affiliation: Department of Pathology, Duke University, Durham, NC, USA.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Foo
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.|Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Garcia-Blanco
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.|Department of Genitourinary Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.|Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C114750:TCF20 protein, human; D014157:Transcription Factors; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: Snail; androgen receptor; castration resistance; enzalutamide; metastasis