Home News About Us Contact Contributors Disclaimer Privacy Policy Help FAQ

Quick Search
My eDoc
Session History
Support Wiki
Direct access to
document ID:

          Display Documents

ID: 207609.0, MPI für biophysikalische Chemie / Molekulare Biologie (Dr. Thomas M. Jovin)
Decreased accessibility and lack of activation of erbB2 in JIMT-1, a Herceptin-resistant, MUC-4-expressing breast cancer cell line
Authors:Nagy, P.; Friedlaender, E.; Tanner, M.; Kapanen, A. I.; Carraway, K. L.; Isola, J.; Jovin, T. M.
Date of Publication (YYYY-MM-DD):2005-02
Title of Journal:Cancer Research
Issue / Number:2
Start Page:473
End Page:482
Review Status:not specified
Audience:Not Specified
Abstract / Description: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 ~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.
Free Keywords:erbB2/HER2; breast cancer; MUC4; RNA interference; trastuzumab/Herceptin resistance
Last Change of the Resource (YYYY-MM-DD):2005-02-07
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/Abt. Thomas Jovin / 060
External Affiliations:Department of Biophysics and Cell Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; Laboratory of Cancer Biology, Institute of Medical Technology, Tampere University and Tampere University Hospital, Tampere, Finland; and Department of Cell Biology and Anatomy, University of Miami, School of Medicine, Miami, Florida, USA
The scope and number of records on eDoc is subject to the collection policies defined by each institute - see "info" button in the collection browse view.