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RESEARCH PRODUCT

MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation

Melissa M. WolfMellissa J. NixonAngel Guerrero-zotanoMelinda E. SandersVioleta SanchezKatherine E. HutchinsonJeffrey C. RathmellCarlos L. ArteagaKyungmin LeeLuis J. SchwarzStephen W. FesikGabriela AndrejevaJustin M. BalkoMonica V. EstradaHenry L. GomezJennifer M. GiltnaneAna LluchTaekyu LeeJ. Alejandro Pérez-fidalgo

subject

0301 basic medicinePhysiologyMice NudeTriple Negative Breast NeoplasmsOxidative phosphorylationTumor initiationMitochondrionBiologyOxidative PhosphorylationArticleProto-Oncogene Proteins c-myc03 medical and health sciencesCancer stem cellCell Line TumorAnimalsHumansMCL1Molecular BiologyTriple-negative breast cancerchemistry.chemical_classificationReactive oxygen speciesCell BiologyMitochondria030104 developmental biologychemistryDrug Resistance NeoplasmNeoplastic Stem CellsCancer researchMyeloid Cell Leukemia Sequence 1 ProteinFemaleStem cellReactive Oxygen Species

description

Summary Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo . These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.

yearjournalcountryeditionlanguage
2017-10-01Cell Metabolism
https://doi.org/10.1016/j.cmet.2017.09.009