title: Identification of caveolin-1 as a potential causative factor in the generation of trastuzumab resistance in breast cancer cells.
abstract: The oncogenic tyrosine kinase receptor ErbB2 is a prognostic factor and target for breast cancer therapeutics. In contrast with the other ErbB receptors, ErbB2 is hardly internalized by ligand induced mechanisms, indicating a prevalent surface expression. Elevated levels of ErbB2 in tumor cells are associated with its defective endocytosis and down regulation. Here we show that caveolin-1 expression in breast cancer derived SKBR-3 cells (SKBR-3/Cav-1) facilitates ligand induced ErbB2 endocytosis using an artificial peptide ligand EC-eGFP. Similarly, stimulation with humanized anti ErbB2 antibody Trastuzumab (Herceptin) was found to be internalized and co-localized with caveolin-1 in SKBR-3/Cav-1 cells. Internalized EC-eGFP and Trastuzumab in SKBR-3/Cav-1 cells were then delivered via caveolae to the caveolin-1 containing early endosomes. Consequently, attenuated Fc receptor mediated ADCC functions were observed when exposed to Trastuzumab and EC-Fc (EC-1 peptide conjugated to Fc part of human IgG). On the other hand, this caveolae dependent endocytic synergy was not observed in parental SKBR-3 cells. Therefore, caveolin-1 expression in breast cancer cells could be a predictive factor to estimate how cancer cells are likely to respond to Trastuzumab treatment.
authors.affiliation: 1. Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
authors.forename: Sreeja C
authors.initials: SC
authors.lastname: Sekhar
authors.forename: Tomonari
authors.initials: T
authors.lastname: Kasai
authors.forename: Ayano
authors.initials: A
authors.lastname: Satoh
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shigehiro
authors.forename: Akifumi
authors.initials: A
authors.lastname: Mizutani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murakami
authors.forename: Bishoy Ya
authors.initials: BY
authors.lastname: El-Aarag
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer
authors.forename: Rafael
authors.initials: R
authors.lastname: de Llorens
authors.forename: Masaharu
authors.initials: M
authors.lastname: Seno
keywords: Antibody dependent cell mediated cytotoxicity (ADCC); Caveolin-1; Ec-eGFP; ErbB2; Trastuzumab.; internalization