Doxorubicin Resistance Reprograms Triple‐Negative Breast Cancer Cell Metabolism via the Fatty Acid β‐Oxidation (FAO)‐CD36 Regulatory Circuit: Relevance of Enhanced FAO on Tumor Cell Invasiveness

ABSTRACT Chemotherapy remains the frontline treatment strategy for triple‐negative breast cancer (TNBC). However, the aggressive nature of TNBC, due to metabolic reprogramming, is often associated with chemoresistance, which limits treatment efficacy. Herein, we investigated the impact of altered lipid homeostasis, in particular, the fatty acid β‐oxidation (FAO) pathway, during doxorubicin (Dox)‐induced chemoresistance and its effect on drug retention and efficacy in TNBC cells. Results indicate that Dox‐induced chemoresistance in MDA‐MB‐231 cells and an in vivo Dox‐resistance breast cancer model in SCID mice are associated with a marked upregulation of FAO. Intriguingly, the basal levels of carnitine palmitoyltransferase 1 (CPT1; a rate‐limiting enzyme of FAO), CD36, (a fatty acid translocase), FAO‐related gene transcript levels, and acetyl‐CoA production were significantly elevated with increased degree of Dox resistance. These changes were paralleled by enhanced uptake of fatty acids and their oxidation. Dox‐resistance in TNBC cells was associated with enhanced mitochondrial respiration, possibly due to increased activities of complex I and IV. Conversely, inhibition of CPT1 by etomoxir caused increased intracellular Dox retention, leading to Dox‐induced cytotoxicity and attenuating the invasiveness of TNBC cells. Importantly, FAO‐derived ATP levels, compared to glucose‐derived ATP, seem to enhance the invasiveness of Dox‐resistant cells. Mechanistically, Dox‐resistance potentiated FAO via CREB activation, which in turn led to the enhancement of the PGC1α/PPARα/CD36‐CPT1 axis. Taken together, Dox‐resistance reprograms cellular metabolism towards FAO regulatory circuit sustaining the mitochondrial bioenergetics, promoting drug efflux, and accentuating breast cancer progression. Based on these findings, it is possible that FAO inhibitors effectively combat drug‐induced TNBC chemoresistance.