三阴性乳腺癌
PI3K/AKT/mTOR通路
癌症研究
蛋白激酶B
MAPK/ERK通路
乳腺癌
下调和上调
细胞凋亡
医学
癌症
生物
信号转导
神经酰胺
细胞生物学
内科学
生物化学
基因
作者
Shan Zhu,Yulin Xu,Lijun Wang,Shichong Liao,Yuan Wang,Manman Shi,Yi Fang Tu,Yuqin Zhou,Wenbin Wei
标识
DOI:10.1186/s12935-020-01735-5
摘要
Abstract Background Clinical management of triple-negative breast cancer (TNBC) patients remain challenging because of the development of chemo-resistance. Identification of biomarkers for risk stratification of chemo-resistance and therapeutic decision-making to overcome such resistance is thus necessary. Methods Retrospective analysis was performed to identify potential stratification biomarkers. The levels of ceramide kinase (CERK) was determined in breast cancer patients. The roles of CERK and its downstream signaling pathways were analysed using cellular and biochemical assays. Results CERK upregulation was identified as a biomarker for chemotherapeutic response in TNBC. A > 2-fold change in CERK (from tumor)/CERK (from normal counterpart) was significantly associated with chemo-resistance (OR = 2.66, 95% CI 1.18–7.34), P = 0.04. CERK overexpression was sufficient to promote TNBC growth and migration, and confer chemo-resistance in TNBC cell lines, although this resistance could be overcome via CERK inhibition. Mechanistic studies suggest that CERK mediates intrinsic resistance and inferior response to chemotherapy in TNBC by regulating multiple oncogenic pathways such as Ras/ERK, PI3K/Akt/mTOR, and RhoA. Conclusions Our work provides an explanation for the heterogeneity of chemo-response across TNBC patients and demonstrates that CERK inhibition offers a therapeutic strategy to overcome treatment resistance.
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