title: Frequent inactivation of cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines.
abstract: OBJECTIVE
  Genome-wide DNA methylation analyses have identified hundreds of candidate DNA-hypermethylated genes in cancer. Comprehensive functional analyses provide an understanding of the biologic significance of this vast amount of DNA methylation data that may allow the determination of key epigenetic events associated with tumorigenesis.
  
  
  METHODS
  To study mechanisms of cysteine dioxygenase type 1 (CDO1) inactivation and its functional significance in breast cancer in a comprehensive manner, we screened for DNA methylation and gene mutations in primary breast cancers and analyzed growth, survival, and reactive oxygen species (ROS) production in breast cancer cells with restored CDO1 function in the context of anthracycline treatment.
  
  
  RESULTS
  DNA methylation-associated silencing of CDO1 in breast cancer is frequent (60%), cancer specific, and correlates with disease progression and outcome. CDO1 function can alternatively be silenced by repressive chromatin, and we describe protein-damaging missense mutations in 7% of tumors without DNA methylation. Restoration of CDO1 function in breast cancer cells increases levels of ROS and leads to reduced viability and growth, as well as sensitization to anthracycline treatment. Priming with 5-azacytidine of breast cancer cells with epigenetically silenced CDO1 resulted in restored expression and increased sensitivity to anthracyclines.
  
  
  CONCLUSIONS
  We report that silencing of CDO1 is a critical epigenetic event that contributes to the survival of oxidative-stressed breast cancer cells through increased detoxification of ROS and thus leads to the resistance to ROS-generating chemotherapeutics including anthracyclines. Our study shows the importance of CDO1 inactivation in breast cancer and its clinical potential as a biomarker and therapeutic target to overcome resistance to anthracyclines.
authors: Department of Surgery, Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors: Jana
authors: J
authors: Jeschke
authors: Heather M
authors: HM
authors: O'Hagan
authors: Wei
authors: W
authors: Zhang
authors: Rajita
authors: R
authors: Vatapalli
authors: Marilia Freitas
authors: MF
authors: Calmon
authors: Ludmila
authors: L
authors: Danilova
authors: Claudia
authors: C
authors: Nelkenbrecher
authors: Leander
authors: L
authors: Van Neste
authors: Ingrid T G W
authors: IT
authors: Bijsmans
authors: Manon
authors: M
authors: Van Engeland
authors: Edward
authors: E
authors: Gabrielson
authors: Kornel E
authors: KE
authors: Schuebel
authors: Andreas
authors: A
authors: Winterpacht
authors: Stephen B
authors: SB
authors: Baylin
authors: James G
authors: JG
authors: Herman
authors: Nita
authors: N
authors: Ahuja
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050558:Cysteine Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D017382:Reactive Oxygen Species; D050558:Cysteine Dioxygenase
references: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6
references: 8790415
references: Cancer Res. 2008 Apr 15;68(8):2764-72
references: 18413743
references: Free Radic Biol Med. 2001 Jun 1;30(11):1286-92
references: 11368926
references: Cancer Res. 2002 Dec 15;62(24):7213-8
references: 12499261
references: Nucleic Acids Res. 2012 May;40(10):4334-46
references: 22278882
references: Cancer Res. 2006 Aug 1;66(15):7490-501
references: 16885346
references: PLoS Genet. 2007 Sep;3(9):1709-23
references: 17892325
references: Cancer Res. 2007 Feb 15;67(4):1472-86
references: 17308085
references: Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E62-9
references: 17327371
references: Nature. 2002 Apr 4;416(6880):552-6
references: 11932749
references: Eur J Cancer. 2011 Dec;47(18):2715-22
references: 21703850
references: Nat Rev Drug Discov. 2009 Jul;8(7):579-91
references: 19478820
references: Cancer Metastasis Rev. 2006 Dec;25(4):695-705
references: 17160708
references: Nature. 2007 Aug 2;448(7153):553-60
references: 17603471
references: Nat Med. 2004 Aug;10(8):789-99
references: 15286780
references: Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S4-11
references: 16341240
references: BMC Cancer. 2010 Jun 01;10:247
references: 20515469
references: PLoS One. 2011;6(8):e23127
references: 21829702
references: Cancer Res. 2004 Jul 1;64(13):4577-84
references: 15231669
references: Drug Resist Updat. 2004 Apr;7(2):97-110
references: 15158766
references: Cancer Res. 2009 Jun 1;69(11):4691-9
references: 19435926
references: Cancer Cell. 2006 Sep;10(3):175-6
references: 16959608
references: Epigenetics. 2012 Jul;7(7):701-9
references: 22647880
references: Breast Cancer Res Treat. 2000 Jan;59(2):163-70
references: 10817351
references: Carcinogenesis. 2004 Nov;25(11):2033-44
references: 15180945
references: Biochem Soc Trans. 2003 Dec;31(Pt 6):1441-4
references: 14641084
references: Amino Acids. 2009 May;37(1):55-63
references: 19011731
references: Chem Commun (Camb). 2007 Aug 28;(32):3338-49
references: 18019494
references: Cancer Cell. 2012 May 15;21(5):655-667
references: 22624715
references: Clin Cancer Res. 2007 Feb 1;13(3):789-94
references: 17289868
references: J Exp Clin Cancer Res. 2007 Mar;26(1):39-50
references: 17550131
references: Cell. 2004 Sep 17;118(6):781-94
references: 15369676
references: J Rheumatol. 1994 Jul;21(7):1192-6
references: 7966056
references: Neurosci Lett. 1990 Mar 2;110(1-2):216-20
references: 2325885
references: J Biol Chem. 1979 Aug 25;254(16):7558-60
references: 38242
references: FEMS Microbiol Lett. 2003 Sep 26;226(2):195-202
references: 14553911
references: Cancer Cell. 2006 Sep;10(3):241-52
references: 16959615
references: J Biol Chem. 2007 Feb 2;282(5):3391-402
references: 17135237
references: Lancet. 1992 Jan 4;339(8784):25-6
references: 1345954
references: Cancer Res. 2011 Apr 15;71(8):2988-99
references: 21363912