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

Kyung min Lee, Jennifer M. Giltnane, Justin M. Balko, Luis J. Schwarz, Angel L. Guerrero-Zotano, Katherine E. Hutchinson, Mellissa J. Nixon, Mónica V. Estrada, Violeta Sánchez, Melinda E. Sanders, Taekyu Lee, Henry Gómez, Ana Lluch, J. Alejandro Pérez-Fidalgo, Melissa Magdalene Wolf, Gabriela Andrejeva, Jeffrey C. Rathmell, Stephen W. Fesik, Carlos L. Arteaga

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)633-647.e7
JournalCell Metabolism
Volume26
Issue number4
DOIs
StatePublished - Oct 3 2017

Fingerprint

Neoplastic Stem Cells
Oxidative Phosphorylation
Triple Negative Breast Neoplasms
Breast Neoplasms
Drug Therapy
Reactive Oxygen Species
Maintenance Chemotherapy
Pharmaceutical Preparations
Drug Resistance
Mitochondria
Respiration
Maintenance
Pharmacology
Neoplasms

Keywords

  • cancer stem cell
  • chemotherapy resistance
  • MCL1
  • mitochondrial respiration
  • MYC
  • triple negative breast cancer

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation. / Lee, Kyung min; Giltnane, Jennifer M.; Balko, Justin M.; Schwarz, Luis J.; Guerrero-Zotano, Angel L.; Hutchinson, Katherine E.; Nixon, Mellissa J.; Estrada, Mónica V.; Sánchez, Violeta; Sanders, Melinda E.; Lee, Taekyu; Gómez, Henry; Lluch, Ana; Pérez-Fidalgo, J. Alejandro; Wolf, Melissa Magdalene; Andrejeva, Gabriela; Rathmell, Jeffrey C.; Fesik, Stephen W.; Arteaga, Carlos L.

In: Cell Metabolism, Vol. 26, No. 4, 03.10.2017, p. 633-647.e7.

Research output: Contribution to journalArticle

Lee, KM, Giltnane, JM, Balko, JM, Schwarz, LJ, Guerrero-Zotano, AL, Hutchinson, KE, Nixon, MJ, Estrada, MV, Sánchez, V, Sanders, ME, Lee, T, Gómez, H, Lluch, A, Pérez-Fidalgo, JA, Wolf, MM, Andrejeva, G, Rathmell, JC, Fesik, SW & Arteaga, CL 2017, 'MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation', Cell Metabolism, vol. 26, no. 4, pp. 633-647.e7. https://doi.org/10.1016/j.cmet.2017.09.009
Lee, Kyung min ; Giltnane, Jennifer M. ; Balko, Justin M. ; Schwarz, Luis J. ; Guerrero-Zotano, Angel L. ; Hutchinson, Katherine E. ; Nixon, Mellissa J. ; Estrada, Mónica V. ; Sánchez, Violeta ; Sanders, Melinda E. ; Lee, Taekyu ; Gómez, Henry ; Lluch, Ana ; Pérez-Fidalgo, J. Alejandro ; Wolf, Melissa Magdalene ; Andrejeva, Gabriela ; Rathmell, Jeffrey C. ; Fesik, Stephen W. ; Arteaga, Carlos L. / MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation. In: Cell Metabolism. 2017 ; Vol. 26, No. 4. pp. 633-647.e7.
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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.

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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.

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KW - chemotherapy resistance

KW - MCL1

KW - mitochondrial respiration

KW - MYC

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