Abstract 802: Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism

Abstract

Abstract Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options like triple negative breast cancer (TNBC). Here we show that BACH1 (BTB and CNC homology1), a heme-binding transcription factor whose expression is enriched in TNBC patients, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the TCA 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 metformin, suppressing growth of both cell line and patient-derived tumor xenografts. Expression of a heme-resistant BACH1 mutant in shBACH1 cells rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumors. Finally, BACH1 gene expression inversely correlates with ETC gene expression in breast cancer patients as well as other tumor types, highlighting the clinical relevance. This study demonstrates that mitochondrial metabolism can be exploited through targeting BACH1 to sensitize breast cancer and potentially other tumor tissues to mitochondrial inhibitors. Citation Format: Jiyoung Lee. Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 802.