title: Flotillin depletion affects ErbB protein levels in different human breast cancer cells.
abstract: The ErbB3 receptor is an important regulator of cell growth and carcinogenesis. Among breast cancer patients, up to 50-70% have ErbB3 overexpression and 20-30% show overexpressed or amplified ErbB2. ErbB3 has also been implicated in the development of resistance to several drugs used against cancers driven by ErbB1 or ErbB2. One of the main challenges in ErbB-targeting therapy is to inactivate signaling mediated by ErbB2-ErbB3 oncogenic receptor complexes. We analyzed the regulatory role of flotillins on ErbB3 levels and ErbB2-ErbB3 complexes in SKBR3, MCF7 and MDA-MB-134-VI human breast cancer cells. Recently, we described a mechanism for interfering with ErbB2 signaling in breast cancer and demonstrated a molecular complex of flotillin scaffolding proteins with ErbB2 and Hsp90. In the present study, flotillins were found to be in a molecular complex with ErbB3, even in cells without the presence of ErbB2 or other ErbB receptors. Depletion of either flotillin-1 or flotillin-2 resulted in downregulation of ErbB3 and a selective reduction of ErbB2-ErbB3 receptor complexes. Moreover, flotillin-2 depletion resulted in reduced activation of Akt and MAPK signaling cascades, and as a functional consequence of flotillin depletion, breast cancer cells showed an impaired cell migration. Altogether, we provide data demonstrating a novel and functional role of flotillins in the regulation of ErbB protein levels and stabilization of ErbB2-ErbB3 receptor complexes. Thus, flotillins are crucial regulators for oncogenic ErbB function and potential targets for cancer treatment.
authors.affiliation: Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
authors.forename: Nagham
authors.initials: N
authors.lastname: Asp
authors.affiliation: Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway. Electronic address: sascha.pust@rr-research.no.
authors.forename: Sascha
authors.initials: S
authors.lastname: Pust
authors.affiliation: Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway; Department of Molecular Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sandvig
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D048049:Extracellular Signal-Regulated MAP Kinases; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C106354:flotillins; C001277:geldanamycin
keywords: Breast cancer; ErbB3 receptor tyrosine kinase; Flotillin