Decitabine response in breast cancer requires efficient drug processing and is not limited by multidrug resistance

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

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1110-1122
Number of pages13
JournalMolecular Cancer Therapeutics
Volume19
Issue number5
DOIs
Publication statusPublished - May 1 2020

Bibliographical note

Funding Information:
Support was provided by grant funding to P. Marcato by the Cancer Research Society in partnership with the Institute of Cancer Research of the Canadian Institutes of Health Research (CIHR; grant number 22185). In addition, support

Publisher Copyright:
© 2020 American Association for Cancer Research.

ASJC Scopus Subject Areas

  • Oncology
  • Cancer Research

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