TY - JOUR
T1 - MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation
AU - Lee, Kyung min
AU - Giltnane, Jennifer M.
AU - Balko, Justin M.
AU - Schwarz, Luis J.
AU - Guerrero-Zotano, Angel L.
AU - Hutchinson, Katherine E.
AU - Nixon, Mellissa J.
AU - Estrada, Mónica V.
AU - Sánchez, Violeta
AU - Sanders, Melinda E.
AU - Lee, Taekyu
AU - Gómez, Henry
AU - Lluch, Ana
AU - Pérez-Fidalgo, J. Alejandro
AU - Wolf, Melissa Magdalene
AU - Andrejeva, Gabriela
AU - Rathmell, Jeffrey C.
AU - Fesik, Stephen W.
AU - Arteaga, Carlos L.
N1 - Funding Information:
This work was supported by Susan G. Komen for the Cure Foundation grant SAC100013 (C.L.A.), a grant from the Breast Cancer Research Foundation , NIH Breast Cancer SPORE grant P50 CA98131 , and Vanderbilt-Ingram Cancer Center Support Grant P30 CA68485 . The Agilent Seahorse Extracellular Flux Analyzer is housed and managed within the Vanderbilt High-Throughput Screening Core Facility, an institutionally supported core, and was funded by NIH Shared Instrumentation Grant 1S10OD018015 . J.M.B. received funding and support for this work from the IBC Network Foundation , Komen Foundation Career Catalyst Research grant 14299052 , and NIH/NCI grant R00-CA181491 . S.W.F. was supported by the NIH Director’s Pioneer Award DP1OD006933 / DP1CA174419 and NCI Experimental Therapeutics (NExT) Program BOA29XS129TO22 under the Leidos Biomed Prime Contract No. HHSN261200800001E. A.L. received funding from Institute of Health Carlos III ( RD12/0036/0070 ).
Publisher Copyright:
© 2017
PY - 2017/10/3
Y1 - 2017/10/3
N2 - 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. MYC and MCL1 are co-amplified in drug-resistant breast cancer. Lee et al. reveal that MYC and MCL1 cooperate to maintain cancer stem cells (CSCs) resistant to chemotherapy by increasing mitochondrial OXPHOS, ROS production, and HIF-1α expression. Inhibition of HIF-1α blocks CSC expansion and restores chemotherapy sensitivity.
AB - 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. MYC and MCL1 are co-amplified in drug-resistant breast cancer. Lee et al. reveal that MYC and MCL1 cooperate to maintain cancer stem cells (CSCs) resistant to chemotherapy by increasing mitochondrial OXPHOS, ROS production, and HIF-1α expression. Inhibition of HIF-1α blocks CSC expansion and restores chemotherapy sensitivity.
KW - MCL1
KW - MYC
KW - cancer stem cell
KW - chemotherapy resistance
KW - mitochondrial respiration
KW - triple negative breast cancer
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U2 - 10.1016/j.cmet.2017.09.009
DO - 10.1016/j.cmet.2017.09.009
M3 - Article
C2 - 28978427
AN - SCOPUS:85032375544
SN - 1550-4131
VL - 26
SP - 633-647.e7
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -