Identification Of Caveolin-1 As A Potential Causative Factor In The Generation Of Trastuzumab Resistance In Breast Cancer Cells

Sreeja C. Sekhar, Tomonari Kasai, Ayano Satoh, Tsukasa Shigehiro, Akifumi Mizutani, Hiroshi Murakami, Bishoy Ya El-Aarag, David S. Salomon, Anna Massaguer, Rafael de Llorens, Masaharu Seno

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)391-401
Number of pages11
JournalJournal of Cancer
Volume4
Issue number5
DOIs
Publication statusPublished - 2013

Keywords

  • Antibody dependent cell mediated cytotoxicity (ADCC)
  • Ec-eGFP
  • ErbB2, Caveolin-1
  • Internalization
  • Trastuzumab.

ASJC Scopus subject areas

  • Oncology

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