title: Deoxycytidine kinase is overexpressed in poor outcome breast cancer and determines responsiveness to nucleoside analogs.
abstract: Only a minority of breast cancer patients responds to chemotherapy and we lack predictive biomarkers that help to select a patient-tailored therapy that takes into consideration the molecular heterogeneity of the cancer type. Responsiveness to the clinically important nucleoside analogs gemcitabine and decitabine may be critically determined by Deoxycytidine kinase (DCK) expression as this enzyme is required to convert the inactive prodrugs into their pharmacologically active forms. Here, we examined whether DCK is differentially expressed in breast cancer and evaluated whether DCK expression levels control responsiveness to these nucleoside analogs in vitro by experimentally modulating DCK expression levels. We examined DCK expression in gene expression data sets of breast tumors including the series of 295 consecutive patients that have been classified into low or high risk for recurrence using the MammaPrint 70 gene profile. We found that DCK is expressed at higher levels in patients having poor clinical outcome as judged by the MammaPrint assay. As such, patients that have a poor prognosis may thus be susceptible to treatment with nucleoside analogs. In support of this, we found a causal relationship between DCK levels and sensitivity to these nucleoside analogs in breast cancer cell lines. The data indicate that breast cancers that are at high risk of recurrence express higher levels of DCK, which we find to be strongly correlated to a favorable response to nucleoside analogs. The data suggest that DCK expression in breast cancer could be exploited to select patients that are likely to respond to treatment with nucleoside analogs.
authors.affiliation: Division of Molecular Carcinogenesis, Center for Biomedical Genetics and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, Amsterdam, The Netherlands.
authors.forename: Ernst-Jan
authors.initials: EJ
authors.lastname: Geutjes
authors.forename: Sun
authors.initials: S
authors.lastname: Tian
authors.forename: Paul
authors.initials: P
authors.lastname: Roepman
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D003842:Deoxycytidine Kinase / Q000235:genetics*; D003853:Deoxyribonucleosides / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011379:Prognosis; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D003853:Deoxyribonucleosides; D003842:Deoxycytidine Kinase