Tamoxifen (TAM) is the first-line endocrine therapy for estrogen receptor-positive (ER+) breast cancer (BC).However,acquired re-sistance occurs in ～50％ cases.Meanwhile,although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients,complex signaling feedback loops exist,which can counter the effectiveness of inhibitors of this pathway.Here,we analyzed signaling pathways and metabolism in ER+ MCF7 BC cell line and their TAM-resistant derivatives that are co-resistant to endoxifen using immunoblotting,quantitative polymerase chain reaction,and the Agilent Seahorse XF Analyzer.We found that activation of AKT and the energy-sensing kinase AMPK was increased in TAM and endoxifen-resistant cells.Furthermore,ERRα/PGC-1β and their target genes MCAD and CPT-1 were increased and regulated by AMPK,which coincided with increased fatty acid oxidation (FAO) and autophagy in TAM-resistant cells.Inhibition of AKT feedback-activates AMPK and ERRα/PGC-1β-MCAD/CPT-1 with a consequent increase in FAO and autophagy that counters the therapeutic effect of endoxifen and AKT inhibitors.Therefore,our results indicate increased activation of AKT and AMPK with metabolic reprogramming and in-creased autophagy in TAM-resistant cells.Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize re-sistant cells to endoxifen.