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Molecular & Cellular Proteomics 8:1436-1449, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Metastasis-related Plasma Membrane Proteins of Human Breast Cancer Cells Identified by Comparative Quantitative Mass Spectrometry^*,

Rikke Leth-Larsen^,, Rikke Lund^,, Helle V. Hansen, Anne-Vibeke Laenkholm^¶, David Tarin^||, Ole N. Jensen^** and Henrik J. Ditzel^,,

From the Medical Biotechnology Center, Institute of Medical Biology, University of Southern Denmark, Winsloewparken 25.3, 5000 Odense C, Denmark,
¶Department of Clinical Pathology, Odense University Hospital, Winsloewparken 15.2, 5000 Odense C, Denmark,
||Moores Cancer Center, University of California, La Jolla, California 92037,
**Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark, and
Department of Oncology, Odense University Hospital, Søndre Boulevard 29, 5000 Odense C, Denmark

The spread of cancer cells from a primary tumor to form metastasis at distant sites is a complex multistep process. The cancer cell proteins and plasma membrane proteins in particular involved in this process are poorly defined, and a study of the very early events of the metastatic process using clinical samples or in vitro assays is not feasible. We have used a unique model system consisting of two isogenic human breast cancer cell lines that are equally tumorigenic in mice; but although one gives rise to metastasis, the other disseminates single cells that remain dormant at distant organs. Membrane purification and comparative quantitative LC-MS/MS proteomics identified 13 membrane proteins that were expressed at higher levels and three that were underexpressed in the metastatic compared with the non-metastatic cell line from a total of 1919 identified protein entries. Among the proteins were ecto-5'-nucleotidase (CD73), NDRG1, integrin β1, CD44, CD74, and major histocompatibility complex class II proteins. The altered expression levels of proteins identified by LC-MS/MS were validated using flow cytometry, Western blotting, and immunocyto- and immunohistochemistry. Analysis of clinical breast cancer biopsies demonstrated a significant correlation between high ecto-5'-nucleotidase and integrin β1 expression and poor outcome, measured as tumor spread or distant recurrence within a 10-year follow-up. Further the tissue analysis suggested that NDRG1, HLA-DR, HLA-DRβ, and CD74 were associated with the ER^–/PR^– phenotype represented by the two cell lines. The study demonstrates a quantitative and comparative proteomics strategy to identify clinically relevant key molecules in the early events of metastasis, some of which may prove to be potential targets for cancer therapy.

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