Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis

• Published in: EMBO reports Vol. 16; no. 9; pp. 1145 - 1163
• Main Authors: Chourasia, Aparajita H, Tracy, Kristin, Frankenberger, Casey, Boland, Michelle L, Sharifi, Marina N, Drake, Lauren E, Sachleben, Joseph R, Asara, John M, Locasale, Jason W, Karczmar, Gregory S, Macleod, Kay F
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01.09.2015; Nature Publishing Group UK; Springer Nature B.V; John Wiley & Sons, Ltd
• Subjects: Angiogenesis; Animals; Autophagy; Biomarkers, Tumor - analysis; BNip3; Breast cancer; Defects; Disease Progression; EMBO03; EMBO07; Female; Genes; Glycolysis; HIF-1α; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; invasive carcinoma; Lung Neoplasms - secondary; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastasis; Mice; Mitochondria; Mitochondrial Proteins - deficiency; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitophagy; Neoplasm Metastasis; Neovascularization, Pathologic - metabolism; Prognosis; Reactive Oxygen Species - metabolism; Rodents; ROS; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumors; HIF‐1α; mitophagy; invasive carcinoma; BNip3; glycolysis; ROS; breast cancer
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201540759

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‐1α and Hif target genes, including those involved in glycolysis and angiogenesis—two 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 dysfunction—caused by defects in mitophagy—can promote the Warburg effect and tumor progression, and suggest better approaches to stratifying TNBC for treatment. Synopsis This study shows that BNip3 loss and the ensuing defects in mitophagy lead to ROS production, Hif transcriptional responses and mammary tumor progression. BNIP3 deletion is a prognostic marker of metastatic potential in triple negative breast cancer. Elevated ROS production by dysfunctional mitochondria in BNip3 null tumors results in increased Hif‐1α levels and increased tumor progression to invasiveness. This novel negative feedback loop between BNip3 and Hif‐1α limits the oncogenic activity of Hif‐1 in glycolysis and angiogenesis. Defective mitochondria and aerobic glycolysis arising from loss of BNip3 is associated with increased dependence on autophagy for survival. BNIP3 is focally deleted in triple negative breast cancer and, together with high HIF‐1α levels, strongly predicts progression to metastasis in TNBC patients. Graphical Abstract This study shows that BNip3 loss and the ensuing defects in mitophagy lead to ROS production, Hif transcriptional responses and mammary tumor progression. BNIP3 deletion is a prognostic marker of metastatic potential in triple negative breast cancer.