title: Androgen receptor signaling regulates DNA repair in prostate cancers.
abstract: We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining.
  
  
  CONCLUSIONS
  We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.
authors.affiliation: 1Human Oncology Pathogenesis Program, 2Developmental Biology Program, and 3Immunology Program; Departments of 4Radiation Oncology, 5Medicine, 6Surgery, and 7Pathology; 8Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center; 9Department of Genetics, Albert Einstein College of Medicine, New York, New York; 10Department of Genetics; and 11Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: William R
authors.initials: WR
authors.lastname: Polkinghorn
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Man X
authors.initials: MX
authors.lastname: Lee
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kass
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Spratt
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Iaquinta
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Arora
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Yen
authors.forename: Ling
authors.initials: L
authors.lastname: Cai
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Philip A
authors.initials: PA
authors.lastname: Watson
authors.forename: Neel P
authors.initials: NP
authors.lastname: Shah
authors.forename: Sho
authors.initials: S
authors.lastname: Fujisawa
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Goglia
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gopalan
authors.forename: Haley
authors.initials: H
authors.lastname: Hieronymus
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.forename: Peter T
authors.initials: PT
authors.lastname: Scardino
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zelefsky
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D015741:Metribolone / Q000627:therapeutic use; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D011839:Radiation, Ionizing; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen; D015741:Metribolone
references.citation: Mol Cell Biol. 2004 Nov;24(21):9305-16
references.pmid: 15485900
references.citation: Cancer Res. 2012 Mar 15;72(6):1494-503
references.pmid: 22266222
references.citation: Cancer Cell. 2010 Jul 13;18(1):11-22
references.pmid: 20579941
references.citation: Genes Dev. 1999 Oct 15;13(20):2633-8
references.pmid: 10541549
references.citation: N Engl J Med. 2011 May 26;364(21):1995-2005
references.pmid: 21612468
references.citation: Cancer Cell. 2011 May 17;19(5):575-86
references.pmid: 21575859
references.citation: Nature. 2012 Jul 12;487(7406):239-43
references.pmid: 22722839
references.citation: Int J Radiat Oncol Biol Phys. 2001 Nov 15;51(4):1002-7
references.pmid: 11704324
references.citation: N Engl J Med. 1997 Jul 31;337(5):295-300
references.pmid: 9233866
references.citation: Clin Cancer Res. 2013 Mar 15;19(6):1547-56
references.pmid: 23349316
references.citation: Nucleic Acids Res. 2010 Oct;38(18):e178
references.pmid: 20802226
references.citation: Mol Cell Biol. 2013 Jan;33(1):111-26
references.pmid: 23109425
references.citation: Mol Cell Biol. 1996 Jan;16(1):258-69
references.pmid: 8524303
references.citation: Urol Oncol. 2008 Sep-Oct;26(5):522-9
references.pmid: 18774467
references.citation: BMC Bioinformatics. 2011 Aug 04;12:323
references.pmid: 21816040
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10820-5
references.pmid: 9724788
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Cancer Cell. 2006 Oct;10(4):321-30
references.pmid: 17010675
references.citation: Mol Cell Biol. 1993 Jul;13(7):3900-6
references.pmid: 8321197
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11890-5
references.pmid: 12185249
references.citation: J Urol. 2008 Apr;179(4):1368-73; discussion 1373
references.pmid: 18289585
references.citation: Cancer Discov. 2012 Dec;2(12):1134-49
references.pmid: 22993403
references.citation: N Engl J Med. 2012 Sep 27;367(13):1187-97
references.pmid: 22894553
references.citation: Cell. 2009 Dec 11;139(6):1069-83
references.pmid: 19962179
references.citation: Cancer Cell. 2013 Jan 14;23(1):35-47
references.pmid: 23260764
references.citation: Science. 2009 May 8;324(5928):787-90
references.pmid: 19359544
references.citation: N Engl J Med. 2011 Jul 14;365(2):107-18
references.pmid: 21751904