title: Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer.
abstract: As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biological characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in PCa etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy, antiandrogens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand-binding domain. This review focuses on the etiology, characterization, biological properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.
authors.affiliation: Departments of Molecular Genetics and MedicineDuke University, 213 Research Dr, 0045 CARL Building, Durham, North Carolina 27710, USADepartment of MedicineDuke Cancer Institute, Duke University, Durham, North Carolina, USAMasonic Cancer CenterUniversity of Minnesota Masonic Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USADepartment of Laboratory Medicine and PathologyUniversity of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Ware
authors.affiliation: Departments of Molecular Genetics and MedicineDuke University, 213 Research Dr, 0045 CARL Building, Durham, North Carolina 27710, USADepartment of MedicineDuke Cancer Institute, Duke University, Durham, North Carolina, USAMasonic Cancer CenterUniversity of Minnesota Masonic Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USADepartment of Laboratory Medicine and PathologyUniversity of Minnesota, Minneapolis, Minnesota, USADepartments of Molecular Genetics and MedicineDuke University, 213 Research Dr, 0045 CARL Building, Durham, North Carolina 27710, USADepartment of MedicineDuke Cancer Institute, Duke University, Durham, North Carolina, USAMasonic Cancer CenterUniversity of Minnesota Masonic Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USADepartment of Laboratory Medicine and PathologyUniversity of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Garcia-Blanco
authors.affiliation: Departments of Molecular Genetics and MedicineDuke University, 213 Research Dr, 0045 CARL Building, Durham, North Carolina 27710, USADepartment of MedicineDuke Cancer Institute, Duke University, Durham, North Carolina, USAMasonic Cancer CenterUniversity of Minnesota Masonic Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USADepartment of Laboratory Medicine and PathologyUniversity of Minnesota, Minneapolis, Minnesota, USADepartments of Molecular Genetics and MedicineDuke University, 213 Research Dr, 0045 CARL Building, Durham, North Carolina 27710, USADepartment of MedicineDuke Cancer Institute, Duke University, Durham, North Carolina, USAMasonic Cancer CenterUniversity of Minnesota Masonic Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USADepartment of Laboratory Medicine and PathologyUniversity of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: Departments of Molecular Genetics and MedicineDuke University, 213 Research Dr, 0045 CARL Building, Durham, North Carolina 27710, USADepartment of MedicineDuke Cancer Institute, Duke University, Durham, North Carolina, USAMasonic Cancer CenterUniversity of Minnesota Masonic Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USADepartment of Laboratory Medicine and PathologyUniversity of Minnesota, Minneapolis, Minnesota, USADepartments of Molecular Genetics and MedicineDuke University, 213 Research Dr, 0045 CARL Building, Durham, North Carolina 27710, USADepartment of MedicineDuke Cancer Institute, Duke University, Durham, North Carolina, USAMasonic Cancer CenterUniversity of Minnesota Masonic Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USADepartment of Laboratory Medicine and PathologyUniversity of Minnesota, Minneapolis, Minnesota, USA dehm@umn.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D018450:Disease Progression; D014644:Genetic Variation; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
chemical_list: C410798:AR protein, human; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen
keywords: AR variants; androgen receptor; castration resistant prostate cancer; epithelial to mesenchymal transition; metastasis; splice variants