J Cancer 2013; 4(5):391-401. doi:10.7150/jca.6470

Research Paper

Identification of Caveolin-1 as a Potential Causative Factor in the Generation of Trastuzumab Resistance in Breast Cancer Cells

Sreeja C Sekhar1, Tomonari Kasai1✉, Ayano Satoh1, Tsukasa Shigehiro1, Akifumi Mizutani1, Hiroshi Murakami1, Bishoy YA El-Aarag2, David S. Salomon3, Anna Massaguer4, Rafael de Llorens4, Masaharu Seno1

1. Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
2. Department of Chemistry, Faculty of Science, Menofia University, Egypt.
3. Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 2702, USA.
4. Biochemistry and Molecular Biology Unit, Department of Biology, Girona University, Girona 17071, Spain.

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.

Keywords: ErbB2, Caveolin-1, Antibody dependent cell mediated cytotoxicity (ADCC), internalization, Ec-eGFP, Trastuzumab.

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How to cite this article:
Sekhar SC, Kasai T, Satoh A, Shigehiro T, Mizutani A, Murakami H, El-Aarag BY, Salomon DS, Massaguer A, de Llorens R, Seno M. Identification of Caveolin-1 as a Potential Causative Factor in the Generation of Trastuzumab Resistance in Breast Cancer Cells. J Cancer 2013; 4(5):391-401. doi:10.7150/jca.6470. Available from http://www.jcancer.org/v04p0391.htm