Flotillins as regulators of ErbB2 levels in breast cancer
| Autor: | M Jenstad, Knut Liestøl, Tove Irene Klokk, Bjørn Erikstein, Kirsten Sandvig, L Tcatchoff, Björn Risberg, Sascha Pust, N Musa, B. van Deurs, Håvard E. Danielsen |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
medicine.medical_specialty Receptor ErbB-2 media_common.quotation_subject Blotting Western Breast Neoplasms Transfection Receptor tyrosine kinase Breast cancer Growth factor receptor Internal medicine Cell Line Tumor Genetics medicine Humans Immunoprecipitation HSP90 Heat-Shock Proteins skin and connective tissue diseases Receptor Internalization neoplasms Molecular Biology media_common Tissue microarray Microscopy Confocal biology Membrane Proteins medicine.disease Immunohistochemistry Gene Expression Regulation Neoplastic Endocrinology SKBR3 Tissue Array Analysis Cancer research biology.protein Female Signal Transduction |
| Zdroj: | Oncogene. 32(29) |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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