title: Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation.
abstract: Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Radiology and Molecular the Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Spratt
authors.affiliation: Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Evans
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Davis
authors.affiliation: Department of Radiology and Molecular the Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Doran
authors.affiliation: Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Man Xia
authors.initials: MX
authors.lastname: Lee
authors.affiliation: Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neel
authors.initials: N
authors.lastname: Shah
authors.affiliation: Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.affiliation: Department of Radiology and Molecular the Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carnazza
authors.affiliation: Departments of Urology and Biochemistry/Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: George G
authors.initials: GG
authors.lastname: Klee
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: William
authors.initials: W
authors.lastname: Polkinghorn
authors.affiliation: Departments of Urology and Biochemistry/Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
authors.affiliation: Department of Radiology and Molecular the Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York. sawyersc@mskcc.org lewisj2@mskcc.org.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. sawyersc@mskcc.org lewisj2@mskcc.org.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D020552:Comet Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000096:biosynthesis*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen