Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Nature 2019 Apr;568(7751):254-258
Date
03/08/2019Pubmed ID
30842661Pubmed Central ID
PMC6698916DOI
10.1038/s41586-019-1005-xScopus ID
2-s2.0-85064269030 (requires institutional sign-in at Scopus site) 215 CitationsAbstract
Mitochondrial metabolism is an attractive target for cancer therapy1,2. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC)1,3. Here we show that BTB and CNC homology1 (BACH1)4, a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin5,6, suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours7. Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors.
Author List
Lee J, Yesilkanal AE, Wynne JP, Frankenberger C, Liu J, Yan J, Elbaz M, Rabe DC, Rustandy FD, Tiwari P, Grossman EA, Hart PC, Kang C, Sanderson SM, Andrade J, Nomura DK, Bonini MG, Locasale JW, Rosner MRMESH terms used to index this publication - Major topics in bold
AnimalsBasic-Leucine Zipper Transcription Factors
Citric Acid Cycle
Electron Transport
Female
Glucose
Hemin
Heterografts
Humans
Metformin
Mice
Mice, Nude
Mitochondria
Proteolysis
Triple Negative Breast Neoplasms
Xenograft Model Antitumor Assays