鞘脂
三苯氧胺
神经酰胺
癌症研究
乳腺癌
雌激素受体
PI3K/AKT/mTOR通路
生物
癌症
细胞凋亡
内科学
细胞生物学
信号转导
医学
生物化学
作者
Cheng Huang,Liangping Su,Yitian Chen,Sangqing Wu,Ruipu Sun,Qiuping Xu,Xiaoyi Qiu,Ciqiu Yang,Xiangbin Kong,Hongquan Qin,Xinbao Zhao,Xue Jiang,Kun Wang,Yinghua Zhu,Ping‐Pui Wong
标识
DOI:10.1016/j.phrs.2022.106558
摘要
Dysregulated sphingolipid metabolism contributes to ER+ breast cancer progression and therapeutic response, whereas its underlying mechanism and contribution to tamoxifen resistance (TAMR) is unknown. Here, we establish sphingolipid metabolic enzyme CERK as a regulator of TAMR in breast cancer. Multi-omics analysis reveals an elevated CERK driven sphingolipid metabolic reprogramming in TAMR cells, while high CERK expression associates with worse patient prognosis in ER+ breast cancer. CERK overexpression confers tamoxifen resistance and promotes tumorigenicity in ER+ breast cancer cells. Knocking out CERK inhibits the orthotopic breast tumor growth of TAMR cells while rescuing their tamoxifen sensitivity. Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/AKT dependent cell proliferation and its driven p53/caspase-3 mediated apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease.
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