Abstract 5497: Effective combination therapy for breast cancer targeting BACH1 and mitochondrial metabolism
Cancer Research(2018)
Abstract
Oxidative phosphorylation is an attractive target for cancer therapy. Reprogramming metabolic pathways by promoting oxidative phosphorylation 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, a heme-binding transcription factor whose expression is enriched in patients with TNBC, inhibits oxidative phosphorylation through direct transcriptional regulation of electron transport chain (ETC) gene expression. Treatment of cells with hemin, which induces BACH1 degradation, mimics BACH1 depletion with shRNA. Pretreatment of TNBC tumors with BACH1 shRNA or hemin overcame resistance to metformin, an anti-diabetic drug, and abolished the growth of both cell line and patient-derived tumor xenografts. BACH1 gene expression inversely correlated with ETC gene expression in breast cancer patients as well as other tumor types, highlighting the clinical relevance. This study demonstrates that oxidative phosphorylation represents an Achilles heel that can be exploited through targeting BACH1 to sensitize breast cancer and potentially other tumor tissues to mitochondrial inhibitors. Citation Format: Jiyoung Lee, Ali Yesilkanal, Casey Frankenberger, Mohamad Elbaz, Daniel Rabe, Jielin Yan, Felicia Rustandy, Peter Hart, Christie Kang, Elizabeth Grossman, Jason Locasale, Daniel Nomura, Marcelo Bonini, Marsha Rosner. Effective combination therapy for breast cancer targeting BACH1 and mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5497.
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Key words
breast cancer,effective combination therapy,metabolism,bach1
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