Frequent inactivation of Cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines

Jana Jeschke, Heather M. O'Hagan, Wei Zhang, Rajita Vatapalli, Marilia Freitas Calmon, Ludmila Danilova, Claudia Nelkenbrecher, Leander Van Neste, Ingrid T G W Bijsmans, Manon Van Engeland, Edward Gabrielson, Kornel E. Schuebel, Andreas Winterpacht, Stephen B. Baylin, James G. Herman, Nita Ahuja

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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. Conclusion: Wereport that silencing of CDO1is 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.

Original languageEnglish (US)
Pages (from-to)3201-3211
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number12
DOIs
StatePublished - Jun 15 2013

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Cysteine Dioxygenase
Anthracyclines
Breast Neoplasms
DNA Methylation
Reactive Oxygen Species
Epigenomics
Azacitidine
Neoplasm Genes
Missense Mutation
Growth
Chromatin
Disease Progression
Neoplasms
Carcinogenesis
Research Design
Biomarkers
Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Frequent inactivation of Cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines. / Jeschke, Jana; O'Hagan, Heather M.; Zhang, Wei; Vatapalli, Rajita; Calmon, Marilia Freitas; Danilova, Ludmila; Nelkenbrecher, Claudia; Van Neste, Leander; Bijsmans, Ingrid T G W; Van Engeland, Manon; Gabrielson, Edward; Schuebel, Kornel E.; Winterpacht, Andreas; Baylin, Stephen B.; Herman, James G.; Ahuja, Nita.

In: Clinical Cancer Research, Vol. 19, No. 12, 15.06.2013, p. 3201-3211.

Research output: Contribution to journalArticle

Jeschke, J, O'Hagan, HM, Zhang, W, Vatapalli, R, Calmon, MF, Danilova, L, Nelkenbrecher, C, Van Neste, L, Bijsmans, ITGW, Van Engeland, M, Gabrielson, E, Schuebel, KE, Winterpacht, A, Baylin, SB, Herman, JG & Ahuja, N 2013, 'Frequent inactivation of Cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines', Clinical Cancer Research, vol. 19, no. 12, pp. 3201-3211. https://doi.org/10.1158/1078-0432.CCR-12-3751
Jeschke, Jana ; O'Hagan, Heather M. ; Zhang, Wei ; Vatapalli, Rajita ; Calmon, Marilia Freitas ; Danilova, Ludmila ; Nelkenbrecher, Claudia ; Van Neste, Leander ; Bijsmans, Ingrid T G W ; Van Engeland, Manon ; Gabrielson, Edward ; Schuebel, Kornel E. ; Winterpacht, Andreas ; Baylin, Stephen B. ; Herman, James G. ; Ahuja, Nita. / Frequent inactivation of Cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 12. pp. 3201-3211.
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abstract = "Purpose: 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. Experimental Design: 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. Conclusion: Wereport that silencing of CDO1is 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.",
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T1 - Frequent inactivation of Cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines

AU - Jeschke, Jana

AU - O'Hagan, Heather M.

AU - Zhang, Wei

AU - Vatapalli, Rajita

AU - Calmon, Marilia Freitas

AU - Danilova, Ludmila

AU - Nelkenbrecher, Claudia

AU - Van Neste, Leander

AU - Bijsmans, Ingrid T G W

AU - Van Engeland, Manon

AU - Gabrielson, Edward

AU - Schuebel, Kornel E.

AU - Winterpacht, Andreas

AU - Baylin, Stephen B.

AU - Herman, James G.

AU - Ahuja, Nita

PY - 2013/6/15

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N2 - Purpose: 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. Experimental Design: 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. Conclusion: Wereport that silencing of CDO1is 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.

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