Silibinin induces metabolic crisis in triple negative breast cancer cells by modulating EGFR-MYC-TXNIP axis: potential therapeutic implications.

: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment modalities and poor prognosis. Metabolic reprogramming in cancer is considered a hallmark of therapeutic relevance. Here, we report that silibinin disrupts metabolic reprogramming in TNBC cells by modulating EGFR-MYC-TXNIP signaling. Metabolic assays combined with LC-MS based metabolomics revealed that silibinin inhibits glycolysis and other key bioenergetic and biosynthetic pathways, to induce metabolic catastrophe in TNBC cells. Consequently, silibinin-induced metabolic suppression resulted in decreased cell biomass, proliferation and stem cell properties. Mechanistically, we identify EGFR-MYC-TXNIP as an important regulator of TNBC metabolism and mediator of inhibitory effects of silibinin. Highlighting the clinical relevance of our observations, analysis of METABRIC dataset revealed deregulation of EGFR-MYC-TXNIP axis in TNBC and association of EGFRhigh -MYChigh -TXNIPlow signature with aggressive glycolytic metabolism and poor disease-specific- and metastasis free survival. Importantly, combination treatment of silibinin or 2-deoxyglucose (glycolysis inhibitor) with paclitaxel synergistically inhibited proliferation of TNBC cells. Together, our results highlight the importance of EGFR-MYC-TXNIP axis in regulating TNBC metabolism, demonstrate the anti-TNBC activity of silibinin and argue in favor of targeting metabolic vulnerabilities of TNBC, at least in combination with conventional chemotherapeutic drugs, to effectively treat TNBC patients.