Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism

Jiyoung Lee ¹, Ali E Yesilkanal ¹, Joseph P Wynne ¹, Casey Frankenberger ¹, Juan Liu ², Jielin Yan ¹, Mohamad Elbaz ¹, Daniel C Rabe ¹, Felicia D Rustandy ¹, Payal Tiwari ¹, Elizabeth A Grossman ³, Peter C Hart ⁴, Christie Kang ⁴, Sydney M Sanderson ², Jorge Andrade ⁵, Daniel K Nomura ³, Marcelo G Bonini ⁴, Jason W Locasale ², Marsha Rich Rosner ⁶

Affiliations

¹ Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
² Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
³ Department of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA, USA.
⁴ Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
⁵ Center for Research Informatics, University of Chicago, Chicago, IL, USA.
⁶ Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. m-rosner@uchicago.edu.

PMID: 30842661
27 citations

Abstract

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.

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