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

Abstract

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.

Exploration of prognosis and immunometabolism landscapes in ER+ breast cancer based on a novel lipid metabolism-related signature

“…Most of the included genes have been reported to exert protumor functions and are associated with prognosis in a variety of malignant diseases, including BC (55)(56)(57)(58)(59). For example, CPT1A, the rate-limiting enzyme during FAO, has been found to promote cell proliferation and survival in luminal BC (60,61). Serum CPT1A levels are also associated with the tumor burden of BC (62).…”

Targeting c-Jun inhibits fatty acid oxidation to overcome tamoxifen resistance in estrogen receptor-positive breast cancer

“…Given that CPT1A-enhanced FAO can promote the acquisition of malignant phenotypes such as cell proliferation and tamoxifen resistance in ER-positive BC cells, CPT1A-FAO might be an effective target for overcoming tamoxifen resistance in BC cells. Recent reports have indicated that pharmacologic inhibition of CPT1A and FAO could prevent ER-positive BC tumour growth and cell proliferation [ 10 , 15 , 39 , 40 ]. In the present study, we demonstrated that inhibition of CPT1A-mediated FAO with a CPT1 inhibitor re-sensitised ER-positive BC cells to tamoxifen therapy, which broadened the therapeutic effects of CPT1A/FAO inhibitors in tumours.…”

“…In addition to epigenetic control, the crosstalk between factors involved in different metabolic processes can regulate CPT1A activity. A recent study revealed that a mitochondrial flavoprotein promoted CPT1A transcription levels by modulating mitochondrial function [ 40 ]. This finding inspired us to conclude that cellular metabolic processes might also exert a regulatory effect on CPT1A expression in ER-positive BC cells.…”

Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors

“…Etomoxir, a well-established CPT1A inhibitor, demonstrates notable antitumour effects across various cancer models. It exhibits efficacy in decreasing the growth and proliferation of endocrine-resistant breast cancer cells by inhibiting FAO [94]. In prostate cancer, etomoxir suppressed cell growth by reducing both FAO and androgen receptor expression levels [93].…”