American Association for Cancer Research
15357163mct190745-sup-226501_2_supp_6105717_q5yvj1.xlsx (234.3 kB)

Up-regulated Hypermethylated genes from Decitabine Response in Breast Cancer Requires Efficient Drug Processing and Is Not Limited by Multidrug Resistance

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posted on 2023-04-03, 18:27 authored by Margaret L. Dahn, Brianne M. Cruickshank, Ainsleigh J. Jackson, Cheryl Dean, Ryan W. Holloway, Steven R. Hall, Krysta M. Coyle, Hillary Maillet, David M. Waisman, Kerry B. Goralski, Carman A. Giacomantonio, Ian C.G. Weaver, Paola Marcato

Genes up-regulated by decitabine treatment in MDA-MB-468, MDA-MB-231, or SUM159 with hypermethylated promoters (TSS200)


Cancer Research Society

Institute of Cancer Research

Canadian Institutes of Health Research

Natural Sciences and Engineering Research Council of Canada


Nova Scotia Health Research Foundation

Killam Laureate scholarship

Nova Scotia Research and Innovation Graduate

Killam Laureate scholarships

Dalhousie Medical Research Foundation

TCGA Research Network



Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBC) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells. In treatment-naïve breast tumors, DCK was higher in TNBCs, and DCK levels were sustained or increased post chemotherapy treatment. This suggests that limited DCK levels will not be a barrier to response in patients with TNBC treated with decitabine as a second-line treatment or in a clinical trial. Methylome analysis revealed that genome-wide, region-specific, tumor suppressor gene–specific methylation, and decitabine-induced demethylation did not predict response to decitabine. Gene set enrichment analysis of transcriptome data demonstrated that decitabine induced genes within apoptosis, cell cycle, stress, and immune pathways. Induced genes included those characterized by the viral mimicry response; however, knockdown of key effectors of the pathway did not affect decitabine sensitivity suggesting that breast cancer growth suppression by decitabine is independent of viral mimicry. Finally, taxol-resistant breast cancer cells expressing high levels of multidrug resistance transporter ABCB1 remained sensitive to decitabine, suggesting that the drug could be used as second-line treatment for chemoresistant patients.

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