title: A hormone-DNA repair circuit governs the response to genotoxic insult.
abstract: Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings show that androgen receptor (AR) activity is induced by DNA damage and promotes expression and activation of a gene expression program governing DNA repair. Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo. Mechanistically, DNA-dependent protein kinase catalytic subunit (DNAPKcs) was identified as a key target of AR after damage, controlling AR-mediated DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these studies identify the AR-DNAPKcs circuit as a major effector of DNA repair and therapeutic resistance and establish a new node for therapeutic intervention in advanced disease.
  
  
  CONCLUSIONS
  The present study identifies for the fi rst time a positive feedback circuit linking hormone action to the DNA damage response and shows the significant impact of this process on tumor progression and therapeutic response. These provocative findings provide the foundation for development of novel nodes of therapeutic intervention for advanced disease.
authors.affiliation: Departments of 1Cancer Biology, 2Urology, and 3Radiation Oncology, and 4Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; 5Michigan Center for Translational Pathology, 6Department of Radiation Oncology, and 7Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Goodwin
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schiewer
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.forename: Randy S
authors.initials: RS
authors.lastname: Schrecengost
authors.forename: Renée
authors.initials: R
authors.lastname: de Leeuw
authors.forename: Sumin
authors.initials: S
authors.lastname: Han
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C497264:Prkdc protein, mouse
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