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

Chaojun Yan; Ronghui Gao; Chuan Gao; Kai Hong; Meng Cheng; Xiaojing Liu; Qing Zhang; Jing Zhang

doi:10.3389/fonc.2023.1105117

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

Front Oncol. 2023 May 3:13:1105117. doi: 10.3389/fonc.2023.1105117. eCollection 2023.

Authors

Chaojun Yan¹, Ronghui Gao¹, Chuan Gao¹, Kai Hong², Meng Cheng³, Xiaojing Liu⁴, Qing Zhang^{5

6}, Jing Zhang¹

Affiliations

¹ 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.
² Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, United States.
⁴ Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, United States.
⁵ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
⁶ Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, United States.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Discussion: 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.

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

Grants and funding

This work is supported by the Fundamental Research Funds for the Central Universities 2042020kf0197 (JZ), ACS RSG-18-059-01-TBE (QZ), National Natural Science Foundation of China 31970737 (JZ) and 32100570 (CY), the Startup Funding from Wuhan University (JZ), Natural Science Foundation of Hubei Province 2020CFA071 (JZ) and the China Postdoctoral Science Foundation 2020M672408 (CY). We also sincerely thank the core facility of the Medical Research Institute at Wuhan University for their technical support.