Journal
EMBO REPORTS
Volume 16, Issue 9, Pages 1145-1163Publisher
WILEY
DOI: 10.15252/embr.201540759
Keywords
BNip3; breast cancer; glycolysis; HIF-1 alpha; invasive carcinoma; mitophagy; ROS
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Funding
- NIH [RO1 CA131188, RO1 CA162405, T32 CA009594, RO1 CA133490]
- University of Chicago Medical Scientist Training Program
- Human Tissue Resource Center, Digital Light Microscopy, Flow Cytometry and the Small Animal Imaging Core Facilities through the University of Chicago Cancer Center Support Grant [P30 CA014599]
- [T32 DK780073]
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BNip3 is a hypoxia-inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BNip3 in a clinically relevant mouse model of mammary tumorigenesis. BNip3 delays primary mammary tumor growth and progression by preventing the accumulation of dysfunctional mitochondria and resultant excess ROS production. In the absence of BNip3, mammary tumor cells are unable to reduce mitochondrial mass effectively and elevated mitochondrial ROS increases the expression of Hif-1 alpha and Hif target genes, including those involved in glycolysis and angiogenesistwo processes that are also markedly increased in BNip3-null tumors. Glycolysis inhibition attenuates the growth of BNip3-null tumor cells, revealing an increased dependence on autophagy for survival. We also demonstrate that BNIP3 deletion can be used as a prognostic marker of tumor progression to metastasis in human triple-negative breast cancer (TNBC). These studies show that mitochondrial dysfunctioncaused by defects in mitophagycan promote the Warburg effect and tumor progression, and suggest better approaches to stratifying TNBC for treatment.
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