Global gene expression analysis of anthracycline-resistant breast cancer cell lines

Drug resistance in breast cancer is the major obstacle to a successful outcome following chemotherapy treatment. While upregulation of multidrug resistance (MDR) genes is a key component of drug resistance in multiple cancers, the complexity and hierarchy of non-MDR driven drug resistance pathways are still largely unknown. The aim of this study was to identify pathways contributing to anthracycline resistance using isogenic drug resistant breast cancer cell lines. We generated isogenic MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines, which were cross-resistant to doxorubicin and SN-38; the SKBR3 cell line was also resistant to taxanes. Epirubicin-resistant cells were morphologically different from native cells, and had alterations in apoptosis and cell cycle profile. Using gene expression and small-molecule inhibitor analyses we identified deregulation of histone H2A and H2B genes in all four cell lines. These genes contribute to several biological pathways, which include cell cycle, chromosomal maintenance, epigenetics, RNA and mitochondrial transcription. Histone deacetylase and cell cycle/DNA damage small molecule inhibitors reversed resistance and were cytotoxic for all four epirubicin-resistant cell lines confirming that histone and cell cycle pathways are associated with epirubicin resistance. This study has established model systems for investigating drug resistance in all four breast cancer subtypes and revealed key pathways that contribute to anthracycline resistance. The global gene expression analysis included 4 parental (anthracycline sensitive) and 4 resistant breast cancer cell lines, in biological triplicates.

乳腺癌耐药是化疗后达成理想治疗结局的主要障碍。尽管多药耐药（multidrug resistance, MDR）基因上调是多种癌症耐药的核心机制，但非MDR介导的耐药通路的复杂性与层级结构仍未被充分阐释。本研究旨在借助同基因背景的耐药乳腺癌细胞系，挖掘参与蒽环类（anthracycline）药物耐药的信号通路。我们成功构建了MDA-MB-231、MCF7、SKBR3及ZR-75-1这四株同基因表柔比星（epirubicin）耐药乳腺癌细胞系，这些细胞系对多柔比星（doxorubicin）与SN-38均表现出交叉耐药性；其中SKBR3细胞系同时对紫杉烷类（taxanes）药物耐药。表柔比星耐药细胞在形态上与亲本细胞存在显著差异，且凋亡程序与细胞周期谱均发生改变。通过基因表达分析与小分子抑制剂实验，我们在上述四株细胞系中均检测到组蛋白H2A及H2B基因的表达失调。这些基因参与的生物学通路涵盖细胞周期调控、染色体维持、表观遗传修饰、RNA及线粒体转录等多个过程。组蛋白去乙酰化酶抑制剂以及细胞周期/DNA损伤小分子抑制剂可逆转耐药表型，并对四株表柔比星耐药细胞系产生细胞毒性，这证实组蛋白通路与细胞周期通路均与表柔比星耐药密切相关。本研究建立了可用于研究四类乳腺癌亚型耐药性的模型体系，并揭示了参与蒽环类药物耐药的关键通路。本研究的全基因组基因表达分析共纳入4株亲本（蒽环类敏感）乳腺癌细胞系与4株耐药乳腺癌细胞系，所有样本均设置三次生物学重复。

搜集汇总

背景与挑战

背景概述

该数据集通过全局基因表达分析，研究了乳腺癌细胞系中蒽环类药物耐药性的机制。研究基于四种同基因耐药细胞系（MDA-MB-231、MCF7、SKBR3和ZR-75-1），发现组蛋白H2A和H2B基因的失调是关键因素，这些基因影响细胞周期、染色体维护和表观遗传等通路，并证实组蛋白去乙酰化酶和细胞周期/DNA损伤抑制剂可逆转耐药性。数据集包含4个敏感和4个耐药细胞系的生物学三重重复样本，为乳腺癌耐药性研究提供了模型系统。