MassIVE MSV000093890

Complete Public PXD048700

Mitochondrial respiration is a targetable vulnerability of endocrine persistence in ER+ breast cancer

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Description

Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. We observed that persistence occurred stochastically without genetic predisposition. Genome-wide screening in persisters revealed a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration. Proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. Persisters exhibiting residual proliferation in human breast tumors following neoadjuvant endocrine therapy showed increased mitochondrial content. Pharmacological inhibition of oxidative phosphorylation suppressed the tumor-forming potential of persisters and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts, supporting therapeutic targeting of mitochondrial metabolism to help eradicate residual disease. [doi:10.25345/C5GM8205B] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: ER+ ; breast cancer ; mitochondrial respiration ; glycolysis ; oxidative phosphorylation ; fulvestrant ; endocrine therapy

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Principal Investigators:
(in alphabetical order) 		Arminja Kettenbach, The Geisel School of Medicine at Dartmouth, United States
Submitting User: madamo
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