Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis
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...
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| Published in | EMBO reports Vol. 16; no. 9; pp. 1145 - 1163 |
|---|---|
| Main Authors | , , , , , , , , , , |
| 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 | |
| Online Access | Get full text |
| ISSN | 1469-221X 1469-3178 |
| DOI | 10.15252/embr.201540759 |
Cover
| Abstract | 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. |
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| AbstractList | 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. 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 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-1[alpha] levels and increased tumor progression to invasiveness. This novel negative feedback loop between BNip3 and Hif-1[alpha] 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-1[alpha] levels, strongly predicts progression to metastasis in TNBC patients. 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. 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. 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. |
| Author | Sharifi, Marina N Asara, John M Sachleben, Joseph R Tracy, Kristin Locasale, Jason W Boland, Michelle L Frankenberger, Casey Macleod, Kay F Karczmar, Gregory S Chourasia, Aparajita H Drake, Lauren E |
| Author_xml | – sequence: 1 givenname: Aparajita H surname: Chourasia fullname: Chourasia, Aparajita H organization: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA – sequence: 2 givenname: Kristin surname: Tracy fullname: Tracy, Kristin organization: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA – sequence: 3 givenname: Casey surname: Frankenberger fullname: Frankenberger, Casey organization: The Ben May Department for Cancer Research, The University of Chicago, IL, Chicago, USA – sequence: 4 givenname: Michelle L surname: Boland fullname: Boland, Michelle L organization: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA – sequence: 5 givenname: Marina N surname: Sharifi fullname: Sharifi, Marina N organization: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA – sequence: 6 givenname: Lauren E surname: Drake fullname: Drake, Lauren E organization: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA – sequence: 7 givenname: Joseph R surname: Sachleben fullname: Sachleben, Joseph R organization: Biomolecular NMR Facility, The University of Chicago, IL, Chicago, USA – sequence: 8 givenname: John M surname: Asara fullname: Asara, John M organization: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, MA, Boston, USA – sequence: 9 givenname: Jason W surname: Locasale fullname: Locasale, Jason W organization: Division of Nutritional Sciences, Cornell University, NY, Ithaca, USA – sequence: 10 givenname: Gregory S surname: Karczmar fullname: Karczmar, Gregory S organization: Department of Radiology, The University of Chicago, IL, Chicago, USA – sequence: 11 givenname: Kay F surname: Macleod fullname: Macleod, Kay F email: kmacleod@uchicago.edu organization: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26232272$$D View this record in MEDLINE/PubMed |
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| Keywords | HIF‐1α mitophagy invasive carcinoma BNip3 glycolysis ROS breast cancer |
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Nat Rev Mol Biol 12: 9-14 Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, Wang TC, Chen WW, Clish CB, Sabatini DM (2014) Metabolic determinants of cancer cell sensitivity to glucose limitation and Kong, Park, Stephen, Calvani, Cardellina, Monks, Fisher, Shoemaker, Melillo (CR25) 2005; 65 Weinberg, Hamanaka, Wheaton, Weinberg, Joseph, Lopez, Kalyanaraman, Mutlu, Budinger, Chandel (CR49) 2010; 107 Sakurai, He, Matsuzawa, Yu, Maeda, Hardiman, Karin (CR32) 2008; 14 Wong, Gilkes, Zhang, Chen, Wei, Chaturvedi, Fraley, Wong, Khoo, Ng (CR19) 2011; 108 Hamanaka, Chandel (CR48) 2010; 35 Koppenol, Bounds, Dang (CR24) 2011; 11 Zhang, Bosch‐Marce, Shimoda, Tan, Baek, Wesley, Gonzalez, Semenza (CR16) 2008; 283 Schindl, Schoppmann, Samonigg, Hausmaninger, Kwasny, Gnant, Jakesz, Kubista, Birner, Oberhuber (CR45) 2002; 8 Diwan, Krenz, Syed, Wansapura, Ren, Koesters, Li, Kirschenbaum, Hahn, Robbins (CR57) 2007; 117 Vande Velde, Cizeau, Dubik, Alimonti, Brown, Israels, Hakem, Greenberg (CR13) 2000; 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| Snippet | BNip3 is a hypoxia‐inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BNip3 in a... BNip3 is a hypoxia-inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BNip3 in a... |
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| SubjectTerms | 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 |
| Title | Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis |
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