Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

摘要: Purpose: Mutations in the ligand binding domain (LBD) of estrogen receptor α (ER) confer constitutive transcriptional activity and resistance to endocrine therapies breast cancer patients. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed elucidate mechanisms conferring this aggressive phenotype. Experimental Design: Cells constitutively physiologic levels ER activating LBD mutations were generated characterized viability, invasiveness tumor formation vivo. Gene expression profile was studied using microarray RNAseq technologies. Metabolic properties cells assessed global metabolite screen direct measurement metabolic activity. Results: mutated showed increased proliferation, migration vivo tumorogenicity compared WT-ER, even presence estrogen. Expression associated with upregulation genes involved invasion metastases, as well elevation cell metabolism. Indeed, a examination revealed four distinct profiles: WT-ER either untreated or estrogen-treated Mutated-ER estrogen-treated. Pathway analyses indicated elevated TCA cycle 537S-ER cells. Thus, while mostly glucose-dependent, not addicted glucose able utilize glutamine an alternative carbon source. Conclusions:Taken together, indicate estrogen-independent rewiring metabolism by LBD-activating These unique activities may serve potential vulnerability aid development novel treatment strategies overcome resistance.