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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lee, K-M; 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

Published Date

  • October 3, 2017

Published In

Volume / Issue

  • 26 / 4

Start / End Page

  • 633 - 647.e7

PubMed ID

  • 28978427

Pubmed Central ID

  • 28978427

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2017.09.009

Language

  • eng

Conference Location

  • United States