Yan Chaojun, Gao Ronghui, Gao Chuan, Hong Kai, Cheng Meng, Liu Xiaojing, Zhang Qing, Zhang Jing
Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Oncol. 2023 May 3;13:1105117. doi: 10.3389/fonc.2023.1105117. eCollection 2023.
The majority of breast cancers (BCs) expressing estrogen receptor (ER) have shown endocrine resistance. Our previous study demonstrated that ferredoxin reductase (FDXR) promoted mitochondrial function and ER+ breast tumorigenesis. But the underlying mechanism is not clear.
Liquid chromatography (LC) tandem mass spectrometry (MS/MS)-based metabolite profiling was utilized to reveal the metabolites regulated by FDXR. RNA microarray was utilized to determine the potential downstream targets of FDXR. Seahorse XF24 analyzer was performed to analyze the FAO-mediated oxygen consumption rate (OCR). Q-PCR and western blotting assays were used to measure expression levels of FDXR and CPT1A. MTS, 2D colony formation and anchorage-independent growth assays were used to evaluate the effects of FDXR or drug treatments on tumor cell growth of primary or endocrine-resistant breast cancer cells.
We found that depletion of FDXR inhibited fatty acid oxidation (FAO) by suppressing CPT1A expression. Endocrine treatment increased the expression levels of both FDXR and CPT1A. Further, we showed that depletion of FDXR or FAO inhibitor etomoxir treatment reduced primary and endocrine-resistant breast cancer cell growth. Therapeutically, combining endocrine therapy with FAO inhibitor etomoxir synergistically inhibits primary and endocrine-resistant breast cancer cell growth.
We reveal that the FDXR-CPT1A-FAO signaling axis is essential for primary and endocrine-resistant breast cancer cell growth, thus providing a potential combinatory therapy against endocrine resistance in ER+ breast cancer.
大多数表达雌激素受体（ER）的乳腺癌（BC）已表现出内分泌抵抗。我们之前的研究表明，铁氧化还原蛋白还原酶（FDXR）促进线粒体功能和ER + 乳腺肿瘤发生。但其潜在机制尚不清楚。
利用基于液相色谱（LC）串联质谱（MS/MS）的代谢物谱分析来揭示受FDXR调节的代谢物。利用RNA微阵列来确定FDXR的潜在下游靶点。使用海马XF24分析仪分析脂肪酸氧化（FAO）介导的耗氧率（OCR）。采用Q-PCR和蛋白质印迹分析来测量FDXR和CPT1A的表达水平。使用MTS、二维集落形成和非锚定依赖性生长分析来评估FDXR或药物处理对原发性或内分泌抵抗性乳腺癌细胞肿瘤细胞生长的影响。
我们发现，敲低FDXR通过抑制CPT1A表达来抑制脂肪酸氧化（FAO）。内分泌治疗增加了FDXR和CPT1A的表达水平。此外，我们表明，敲低FDXR或用FAO抑制剂依托莫昔芬处理可降低原发性和内分泌抵抗性乳腺癌细胞的生长。在治疗方面，将内分泌治疗与FAO抑制剂依托莫昔芬联合使用可协同抑制原发性和内分泌抵抗性乳腺癌细胞的生长。
我们揭示了FDXR-CPT1A-FAO信号轴对于原发性和内分泌抵抗性乳腺癌细胞生长至关重要，从而为抗ER + 乳腺癌内分泌抵抗提供了一种潜在的联合治疗方法。
