Huang Jianbo, Luo Qingqing, Xiao Yun, Li Hongyuan, Kong Lingquan, Ren Guosheng
Department of Endocrine & Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Department of Oncology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.
Oncotarget. 2017 Nov 21;8(64):108249-108260. doi: 10.18632/oncotarget.22604. eCollection 2017 Dec 8.
Triple negative breast cancer (TNBC) is not sensitive to RAS/RAF/ERK signaling pathway (ERK pathway) targeting therapy, due to the absence of excessive activation of ERK pathway. However, the kinase cascades might be activated after chemotherapy in TNBC. Here we aimed to predict whether ERK pathway targeting therapy could be used as an adjuvant therapy in TNBC.
Within online GEO datasets (GSE43816 and GSE54326), gene set enrichment analysis (GSEA) was performed to detect molecular changes in epirubicin treated TNBC samples and cells, ERK pathway components and regulation genes changes were included.
In epirubicin treated TNBC samples and cells, we found ERK pathway components (eg. MAPK13, MAP3K1, MAPK12, MAPK11 and MAPKAPK3) were obviously enriched, also, expression of ERK pathway positive regulation genes significantly increased (<0.05) and negative regulation genes decreased (<0.05) in epirubicin resistant cells. Moreover, phosphorylated ERK levels were significantly elevated in MDA-MB-231 cells after epirubicin treatment.
ERK signaling pathway was more activated in epirubicin treated TNBC, possibly contributing to the epirubicin resistance in TNBC, it implicated that ERK pathway could be used as an novel candidate for targeting therapy in refractory and relapse TNBC.
三阴性乳腺癌（TNBC）对RAS/RAF/ERK信号通路（ERK通路）靶向治疗不敏感，因为ERK通路不存在过度激活。然而，TNBC在化疗后激酶级联反应可能被激活。在此，我们旨在预测ERK通路靶向治疗是否可作为TNBC的辅助治疗。
在在线GEO数据集（GSE43816和GSE54326）中，进行基因集富集分析（GSEA）以检测表柔比星处理的TNBC样本和细胞中的分子变化，包括ERK通路成分和调控基因的变化。
在表柔比星处理的TNBC样本和细胞中，我们发现ERK通路成分（如MAPK13、MAP3K1、MAPK12、MAPK11和MAPKAPK3）明显富集，此外，在表柔比星耐药细胞中，ERK通路正调控基因的表达显著增加（<0.05），负调控基因的表达减少（<0.05）。此外，表柔比星处理后MDA-MB-231细胞中磷酸化ERK水平显著升高。
在表柔比星处理的TNBC中ERK信号通路更易被激活，这可能导致TNBC对表柔比星耐药，这表明ERK通路可作为难治性和复发性TNBC靶向治疗的新候选靶点。
