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.

中文翻译：

---

地西他滨对乳腺癌的反应需要有效的药物处理，并且不受多药耐药性的限制

DNA 甲基化的失调是乳腺癌的一个既定特征。DNA 去甲基化疗法如地西他滨被提议用于治疗三阴性乳腺癌 (TNBC)，需要确定反应指标。为此，我们在一组 10 个乳腺癌细胞系中表征了地西他滨的作用，并观察了对地西他滨的一系列非亚型特异性敏感性。潜在关键效应物的击倒证明了脱氧胞苷激酶 (DCK) 对乳腺癌细胞中地西他滨反应的要求。在未接受治疗的乳腺肿瘤中，TNBC 中的 DCK 较高，化疗后 DCK 水平持续或增加。这表明，在接受地西他滨作为二线治疗或临床试验的 TNBC 患者中，有限的 DCK 水平不会成为反应的障碍。甲基化组分析显示，全基因组、区域特异性、肿瘤抑制基因特异性甲基化和地西他滨诱导的去甲基化不能预测对地西他滨的反应。转录组数据的基因集富集分析表明，地西他滨诱导细胞凋亡、细胞周期、应激和免疫通路中的基因。诱导基因包括那些以病毒模拟反应为特征的基因；然而，该途径的关键效应物的敲低并不影响地西他滨的敏感性，这表明地西他滨对乳腺癌生长的抑制与病毒模拟无关。最后，