FDXR drives primary and endocrine-resistant tumor cell growth in ER+ breast cancer via CPT1A-mediated fatty acid oxidation

Frontiers in Oncology

Oncology

Kai Hong¹  Qing Zhang²  Xiaojing Liu³  Chaojun Yan⁴  Chuan Gao⁴  Jing Zhang⁴  Ronghui Gao⁴  Meng Cheng⁵ 

[1] Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States;Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, United States;Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, United States;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;Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, United States;

关键词: breast cancer;    endocrine resistance;    ferredoxin reductase;    palmitoyltransferase 1A;    fatty acid oxidation;    combination therapy;   

DOI  :  10.3389/fonc.2023.1105117

 received in 2022-11-22, accepted in 2023-04-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundThe 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.MethodsLiquid 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.ResultsWe 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.DiscussionWe 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.

【 授权许可】

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Copyright © 2023 Yan, Gao, Gao, Hong, Cheng, Liu, Zhang and Zhang