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001-es BibID:BIBFORM004879
Első szerző:Nagy Péter (biofizikus)
Cím:Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line / Nagy, P., Friedlander, E., Tanner, M., Kapanen, A. I., Carraway, K. L., Isola, J., Jovin, T. M.
Dátum:2005
ISSN:0008-5472
Megjegyzések:Overexpression of erbB2 in breast tumors is associated with poor prognosis and is a target of receptor-oriented cancer therapy. Trastuzumab (Herceptin), a monoclonal antibody against a membrane-proximal epitope in the extracellular region of erbB2, shows a therapeutic effect against a fraction of erbB2-amplified breast tumors. Unfortunately, resistance to Herceptin is common, and its cause is as yet unclear. Here we investigated the properties of erbB2 in a Herceptin-resistant cell line, JIMT-1, established from a breast cancer patient showing erbB2 gene amplification and primary resistance to Herceptin. The expression profile of erbB proteins, Herceptin-induced erbB2 internalization, and down-regulation in JIMT-1 were similar to those in Herceptin-sensitive lines. However, the mean number of Herceptin Mab binding sites in JIMT-1 was 1/5 that of the expressed erbB2 molecules, although 5% to 10% of the cells showed a approximately 10-fold higher Herceptin binding than the main population. Herceptin Fab and Mab 2C4, an antibody binding to an epitope in the ectodomain further removed from the membrane, bound more efficiently to JIMT-1 cells than Herceptin Mab, implying that erbB2 was partly masked. The expression of MUC4, a membrane-associated mucin that according to reports contributes to the masking of membrane proteins, was higher in JIMT-1 than in Herceptin-sensitive lines, and its level was inversely correlated with the Herceptin binding capacity of single cells. Knockdown of MUC4 expression by RNA interference increased the binding of Herceptin. Western blotting showed a low level of proteolytic processing, shedding, and tyrosine phosphorylation of erbB2 in JIMT-1. The latter finding may explain its Herceptin-resistant phenotype characterizing both the low and high Herceptin binding subpopulations. We conclude that masking of erbB2 in JIMT-1 leads to diminished Herceptin binding and isolation of erbB2 from its normal interaction and activation partners.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Antibodies
Antibodies,Monoclonal
Antineoplastic Agents
Binding Sites
biosynthesis
Breast Neoplasms
Cell Line
Cell Line,Tumor
Cells
chemistry
Down-Regulation
Drug Resistance,Neoplasm
drug therapy
Enzyme Activation
enzymology
Epitopes
Gene Amplification
Humans
immunology
Membrane Proteins
metabolism
Metalloproteases
Mucins
pharmacology
Phenotype
Phosphorylation
Proteins
Receptor,erbB-2
Research
Support
therapy
Tyrosine
Megjelenés:Cancer Research. - 65 : 2 (2005), p. 473-482. -
További szerzők:Friedländer Elza (1980-) (biofizikus) Tanner, Minna Kapanen, Anita I. Carraway, Kermit L. Isola, Jorma Jovin, Thomas M.
Internet cím:elektronikus változat
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