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Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis
Author(s) -
Chourasia Aparajita H,
Tracy Kristin,
Frankenberger Casey,
Boland Michelle L,
Sharifi Mari,
Drake Lauren E,
Sachleben Joseph R,
Asara John M,
Locasale Jason W,
Karczmar Gregory S,
Macleod Kay F
Publication year - 2015
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201540759
Subject(s) - mitophagy , autophagy , cancer research , tumor progression , biology , carcinogenesis , metastasis , mammary tumor , mitochondrion , angiogenesis , warburg effect , glycolysis , primary tumor , microbiology and biotechnology , cancer , mitochondrial ros , anaerobic glycolysis , breast cancer , cancer cell , endocrinology , apoptosis , genetics , metabolism
Abstract BN ip3 is a hypoxia‐inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BN ip3 in a clinically relevant mouse model of mammary tumorigenesis. BN ip3 delays primary mammary tumor growth and progression by preventing the accumulation of dysfunctional mitochondria and resultant excess ROS production. In the absence of BN ip3, 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 BN ip3‐null tumors. Glycolysis inhibition attenuates the growth of BN ip3‐null tumor cells, revealing an increased dependence on autophagy for survival. We also demonstrate that BNIP 3 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.