Investigating therapy-induced senescence as a reversible escape mechanism of drug resistance in breast cancer cells using high-dose doxorubicin treatment [RNA-seq]

The emergence of drug resistance remains a critical challenge in cancer treatment, significantly contributing to high mortality rates. Here, we investigate therapy-induced senescence (TIS) as a reversible escape mechanism of drug resistance in breast cancer cells. Using high-dose doxorubicin, we induced TIS in MCF7, T47D, MDA-MB-231 and Hs578T breast cancer cell lines. Bulk RNA sequencing revealed a unique transcriptomic profile in TIS cells, distinct from both parental and repopulated cells in every cell line, exposing a small subpopulation of TIS cells with the potential to escape senescence. Gene set enrichment analysis indicated significant downregulation of proliferation-related genes, downregulation of DNA repair pathways, and the upregulation of immune response related genes. MCF7, T47D, MDA-MB-231 and Hs578T control, therapy-induced senescent (TIS) and repopulated cells and also HFF control and therapy-induced senescent cells were analyzed using RNAseq

耐药性的出现仍是癌症治疗领域的关键挑战，亦是癌症高死亡率的重要诱因之一。本研究将治疗诱导性衰老（therapy-induced senescence, TIS）作为乳腺癌细胞产生耐药性的可逆逃逸机制展开探究。我们通过高剂量阿霉素处理，在MCF7、T47D、MDA-MB-231及Hs578T四种乳腺癌细胞系中成功诱导出治疗诱导性衰老表型。批量RNA测序（bulk RNA sequencing）结果显示，治疗诱导性衰老细胞具有独特的转录组特征，在所有受试细胞系中均与亲本细胞及复增殖细胞存在显著差异，并揭示出一小部分具备逃逸衰老潜能的治疗诱导性衰老细胞亚群。基因集富集分析结果表明，增殖相关基因显著下调、DNA修复通路受到显著抑制，而免疫应答相关基因则呈现上调趋势。本研究对MCF7、T47D、MDA-MB-231及Hs578T的对照细胞、治疗诱导性衰老细胞与复增殖细胞，以及HFF对照细胞和治疗诱导性衰老细胞均进行了RNA测序分析。