title: Flotillins as regulators of ErbB2 levels in breast cancer.
abstract: Amplification and overexpression of the receptor tyrosine kinase ErbB2 occur in up to 30% of human breast cancers, and high ErbB2 levels are correlated with poor prognosis for breast cancer patients. In contrast to the epithelial growth factor receptor (ErbB1), ErbB2 is not downregulated by ligand-induced mechanisms. Here we show that flotillins are involved in the stabilization of ErbB2 at the plasma membrane. In SKBR3 breast cancer cells and breast cancer tissue, a positive correlation between flotillin and ErbB2 expression levels could be demonstrated. Moreover, the tissue microarray analyses of biopsies from 194 patients diagnosed with carcinomas of the breast showed that flotillin-2 emerged as a potential predictor of prognosis in breast cancer. Depletion of flotillin-1 and flotillin-2 leads to internalization and degradation of ErbB2. Furthermore, flotillin-1 and -2 were found to be in a molecular complex with ErbB2 and Hsp90. The depletion of one of these proteins results in disruption of this complex, followed by destabilization of ErbB2 at the membrane, and its internalization and degradation. As a consequence, ErbB2-triggered downstream signalling is inhibited. Our data demonstrate a novel mechanism for interfering with ErbB2 signalling, which potentially can have clinical impact.
authors.affiliation: Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Pust
authors.forename: T I
authors.initials: TI
authors.lastname: Klokk
authors.forename: N
authors.initials: N
authors.lastname: Musa
authors.forename: M
authors.initials: M
authors.lastname: Jenstad
authors.forename: B
authors.initials: B
authors.lastname: Risberg
authors.forename: B
authors.initials: B
authors.lastname: Erikstein
authors.forename: L
authors.initials: L
authors.lastname: Tcatchoff
authors.forename: K
authors.initials: K
authors.lastname: Liestøl
authors.forename: H E
authors.initials: HE
authors.lastname: Danielsen
authors.forename: B
authors.initials: B
authors.lastname: van Deurs
authors.forename: K
authors.initials: K
authors.lastname: Sandvig
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C106354:flotillins; C508053:ERBB2 protein, human