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.
Highlights
DNA methylation is essential for gene regulation in normal cells [1]
To first explore the range of sensitivity to decitabine in breast cancer, we treated a panel of 10 cell lines representing estrogen receptor–positive breast cancers (MCF7 and T47D), HER2þ (SKBR3), and triple-negative breast cancers (TNBC) (MDA-MB-231, MDA-MB-468, SUM149, SUM159, MDA-MB-436, MDA-MB-453, and Hs578T)
deoxycytidine kinase (DCK) is required for decitabine response in breast cancer cells and tumors To assess the potential factors which may dictate breast cancer sensitivity to decitabine, we considered the cell-specific factors required for the cytosine analog's incorporation into DNA
Summary
DNA methylation is essential for gene regulation in normal cells [1]. DNA methylation is largely dysregulated with global demethylation contributing to genomic instability and the hypermethylation of CpG islands in the promoters of tumor suppressor genes causing their aberrant silencing [1]. DNA methyltransferases (DNMT) are required for both de novo methylation and maintenance of existing DNA methylation; DNMT upregulation is associated with both cancer and aberrant methylation. Leukemias (AML)], where patients often share common epigenetic perturbations [2]. This has generated interest in using demethylating agents to treat solid tumors, including breast cancers [3]
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