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An osteopontin splice variant induces anchorage independence in human breast cancer cells

Oncogene volume 25, pages 2192–2202 (2006)Cite this article

Abstract

In malignant tumors, metastasis genes are typically deregulated by aberrant expression or splicing. Osteopontin is expressed at high levels by various cancers and contributes importantly to their invasive potential. In contrast, osteopontin derived from host cells induces cellular immunity and could bolster antitumor protection by cytotoxic T lymphocytes. Here we show that breast cancer cells express multiple splice variants of osteopontin. According to RT–PCR analysis of human breast tissue specimens, the splice variant osteopontin-c is a highly specific marker for transformed cells, which is not expressed in their surrounding normal tissue. The full-length form of osteopontin aggregates in the presence of physiologic amounts of calcium and, in this state, leads to enhanced cell adhesion. Ostensibly, this effect is inhibitory for tumor cell dissemination. The shortest splice variant, osteopontin-c, does not aggregate in the presence of calcium and enhances clone formation in soft agar. According to microarray analysis, osteopontin-c induces the expression of oxidoreductases, consistent with protection from anoikis during anchorage-independent growth. These studies define a third functional domain of osteopontin, beside the C-terminal CD44-binding site and the central integrin-binding site. They also provide evidence for a bifunctional character of osteopontin, with the soluble form supporting invasiveness and the aggregated form promoting adhesion.

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Acknowledgements

This study was supported by National Institutes of Health research Grant CA76176 and Department of Defense breast cancer Grant DAMD17-02-0510 to GFW. The collection of tumor specimens was supported in part by USPHS Grant #M01 RR 08084 from the General Clinical Research Centers Program, National Center for Research Resources, NIH. Dr Danny Welch, Birmingham, AL, generously provided the MDA-MB-435 cells.

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  1. B He and M Mirza: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Oncology Research Institute, New England Medical Center, Boston, MA, USA

    B He & G F Weber

  2. University of Cincinnati Medical Center, College of Pharmacy, Cincinnati, OH, USA

    M Mirza & G F Weber

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  1. B He
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  3. G F Weber
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Correspondence to G F Weber.

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He, B., Mirza, M. & Weber, G. An osteopontin splice variant induces anchorage independence in human breast cancer cells. Oncogene 25, 2192–2202 (2006). https://doi.org/10.1038/sj.onc.1209248

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