PDF(Pubmed)
Abstract：
Drug resistance in breast cancer (BC) is a clinical challenge. Exploring the mechanism and identifying a precise predictive biomarker for the drug resistance in BC is critical. Three first-line drug (paclitaxel, doxorubicin and tamoxifen) resistance datasets in BC from GEO were merged to obtain 1,461 differentially expressed genes for weighted correlation network analysis, resulting in identifying ATRX as the hub gene. ATRX is a chromatin remodelling protein, therefore, ATRX-associated transcription factors were explored, thereby identifying the network of AR, GLI3 and GATA2. GO and KEGG analyses revealed immunity, transcriptional regulation and endocrinotherapy/chemotherapy resistance were enriched. Moreover, CIBERSORT revealed immunity regulation was inhibited in the resistance group. ssGSEA showed a significantly lower immune status in the ATRX-Low group compared to the ATRX-High group. Furthermore, the peaks of H3K9me3 ChIP-seq on the four genes were higher in normal tissues than in BC tissues. Notably, the frequency of ATRX mutation was higher than BRCA in BC. Moreover, depressed ATRX revealed worse overall survival and disease-free survival in the human epidermal growth factor receptor 2 (HER2)-/hormone receptor (HR)+ BC. Additionally, depressed ATRX predicted poor results for patients who underwent endocrinotherapy or chemotherapy in the HER2-/HR+ BC subgroup. A nomogram based on ATRX, TILs and ER exhibited a significantly accurate survival prediction ability. Importantly, overexpression of ATRX significantly inhibited the IC50 of the three first-line drugs on MCF-7 cell. Thus, ATRX is an efficient predictive biomarker for endocrinotherapy and chemotherapy resistance in HER2-/HR+ BC and acts by suppressing the AR, GLI3 and GATA2 transcriptional network.
摘要：
乳腺癌（BC）的耐药性是一个临床挑战。探索机制并确定BC耐药性的精确预测生物标志物至关重要。三种一线药物（紫杉醇，合并来自GEO的BC中的多柔比星和他莫昔芬）抗性数据集，以获得1,461个差异表达基因，用于加权相关网络分析，从而确定ATRX为hub基因。ATRX是一种染色质重塑蛋白，因此,ATRX相关转录因子进行了探索，从而识别AR网络，GLI3和GATA2。GO和KEGG分析揭示了免疫力，转录调控和内分泌治疗/化疗耐药被丰富。此外，CIBERSORT显示，抵抗组的免疫调节受到抑制。与ATRX-High组相比，ssGSEA在ATRX-Low组中显示出明显较低的免疫状态。此外，正常组织中H3K9me3ChIP-seq的峰值高于BC组织。值得注意的是,BC中ATRX突变频率高于BRCA。此外，抑制的ATRX显示人类表皮生长因子受体2（HER2）-/激素受体（HR）BC的总体生存率和无病生存率较差。此外,抑郁的ATRX预测HER2-/HR+BC亚组接受内分泌治疗或化疗的患者效果不佳.基于ATRX的列线图，TIL和ER表现出显著准确的生存预测能力。重要的是,ATRX过表达显著抑制三种一线药物对MCF-7细胞的IC50。因此，ATRX是HER2-/HR+BC内分泌治疗和化疗耐药的有效预测生物标志物，通过抑制AR发挥作用，GLI3和GATA2转录网络。
