title: Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2highBreast Cancer.
abstract: Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2highdisease.
  
  
  
  We demonstrate that Her2highcells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2hightumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2highbackground in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2highcells to MitoTam is dependent on the mitochondrial fraction of Her2.
  
  
  
  Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam.
  
  
  
  We propose that the ETC is a suitable therapeutic target in Her2highdisease. Antioxid. Redox Signal. 26, 84-103.
authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .
authors.forename: Katerina
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authors.lastname: Rohlenova
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Karishma
authors.initials: K
authors.lastname: Sachaphibulkij
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .|3 Prague Institute of Chemical Technology , Prague, Czech Republic .|4 Biomedical Research Center, University Hospital , Hradec Kralove, Czech Republic .
authors.forename: Jan
authors.initials: J
authors.lastname: Stursa
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Ayenachew
authors.initials: A
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authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .
authors.forename: Jan
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authors.lastname: Blecha
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Berwini
authors.initials: B
authors.lastname: Endaya
authors.affiliation: 4 Biomedical Research Center, University Hospital , Hradec Kralove, Czech Republic .
authors.forename: Lukas
authors.initials: L
authors.lastname: Werner
authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .
authors.forename: Jiri
authors.initials: J
authors.lastname: Cerny
authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .|2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Renata
authors.initials: R
authors.lastname: Zobalova
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.affiliation: 5 Institute of Physiology , Prague, Czech Republic .
authors.forename: Tomas
authors.initials: T
authors.lastname: Spacek
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Elham
authors.initials: E
authors.lastname: Alizadeh Pesdar
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Maria Nga
authors.initials: MN
authors.lastname: Nguyen
authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .
authors.forename: Magdalena
authors.initials: M
authors.lastname: Vondrusova
authors.affiliation: 6 Institute of Molecular Genetics , Czech Academy of Sciences, Prague, Czech Republic .
authors.forename: Margaryta
authors.initials: M
authors.lastname: Sobol
authors.affiliation: 5 Institute of Physiology , Prague, Czech Republic .
authors.forename: Petr
authors.initials: P
authors.lastname: Jezek
authors.affiliation: 6 Institute of Molecular Genetics , Czech Academy of Sciences, Prague, Czech Republic .
authors.forename: Pavel
authors.initials: P
authors.lastname: Hozak
authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Truksa
authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .
authors.forename: Jakub
authors.initials: J
authors.lastname: Rohlena
authors.affiliation: 2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.affiliation: 1 Institute of Biotechnology , Czech Academy of Sciences, BIOCEV, Vestec, Prague-West, Czech Republic .|2 School of Medical Science, Griffith University , Southport, Australia .
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D045222:Electron Transport Chain Complex Proteins; D042967:Electron Transport Complex I; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen
keywords: HER2; breast cancer; mitochondria; mitochondrially targeted tamoxifen; respirasome