title: Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis.
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.
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA The Committee on Cancer Biology, Chicago, IL, USA.
authors.forename: Aparajita H
authors.initials: AH
authors.lastname: Chourasia
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA The Committee on Cancer Biology, Chicago, IL, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Tracy
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Frankenberger
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA The Committee on Molecular Metabolism and Nutrition, Chicago, IL, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Boland
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA The Committee on Cancer Biology, Chicago, IL, USA.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Sharifi
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA The Committee on Molecular Pathogenesis & Molecular Medicine, Chicago, IL, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Drake
authors.affiliation: Biomolecular NMR Facility, The University of Chicago, Chicago, IL, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Sachleben
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Department of Radiology, The University of Chicago, Chicago, IL, USA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Karczmar
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA The Committee on Cancer Biology, Chicago, IL, USA The Committee on Molecular Metabolism and Nutrition, Chicago, IL, USA kmacleod@uchicago.edu.
authors.forename: Kay F
authors.initials: KF
authors.lastname: Macleod
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D018450:Disease Progression; D005260:Female; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D063306:Mitophagy; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: C508686:BNip3 protein, mouse; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species
keywords: BNip3; HIF‐1α; ROS; breast cancer; glycolysis; invasive carcinoma; mitophagy