Comprehensive characterization of fatty acid oxidation in triple-negative breast cancer: Focus on biological roles and drug modulation

Abstract

Triple-negative breast cancer (TNBC) presents an unmet medical challenge due to poor outcomes and limited treatment options. Metabolic signals are coupled to oncogenesis. Fatty acid oxidation (FAO) plays a crucial role in cancer initiation, progression, metastasis, and therapy resistance, but its precise functions and underlying molecular mechanisms in TNBC remain unclear. Here, we conducted a comprehensive study to investigate the biological roles and drug modulation of FAO in TNBC using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Genomics of Drug Sensitivity in Cancer (GDSC), and Connectivity Map (CMap) databases. We found that altered FAO activity was not related to patient age, clinical stage, tumor mutational burden, microsatellite instability, or homologous recombination deficiency. Nevertheless, upregulated FAO activity correlated with poor prognosis, increased stemness, accelerated cell cycle progression, altered mutation rates of several top 20 most frequently mutated genes, as well as higher activity of pathways involving oncogenic signaling, cellular metabolism, protein turnover, and so forth. Elevated FAO activity also appeared to foster an immunosuppressive microenvironment, influence microbial composition, and confer resistance to chemotherapies. What's more, we identified several compounds that may regulate FAO activity, including the HDAC inhibitor chidamide, which induced FAO activation in TNBC cells. Co-treatment with an FAO inhibitor etomoxir enhanced the combined effects of chidamide with established chemotherapy drugs, as well as their efficacy as single agents in TNBC cells. In conclusion, FAO likely exerts pleiotropic biological effects in TNBC and modulating FAO may offer a promising strategy to improve therapeutic outcomes in TNBC patients.