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Reduction of Raf-1 Kinase Inhibitor Protein Expression Correlates with Breast Cancer Metastasis

Authors' Affiliations: ¹ Beatson Institute for Cancer Research, Signaling and Proteomics Laboratory; ² Centre for Oncology and Applied Pharmacology, Cancer Research UK, Beatson Laboratories; ³ Department of Pathology, Western Infirmary; ⁴ Institute of Biomedical and Life Sciences, Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, Glasgow, United Kingdom; ⁵ Molecular Pathology Laboratory, Department of Pathology, Kuwait University, Faculty of Medicine, Safat, Kuwait

Requests for reprints: Walter Kolch, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom. Phone: 44-141-330-3983; Fax: 44-141-942-6521; E-mail: wkolch{at}beatson.gla.ac.uk.

Purpose: Raf-1 kinase inhibitor protein (RKIP) was originally identified as the first physiologic inhibitor of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway. This pathway regulates fundamental cellular functions, including those that are subverted in cancer cells, such as proliferation, transformation, survival, and metastasis. Recently, RKIP has been recognized as a strong candidate for a metastasis suppressor gene in cell and animal model systems. Therefore, we investigated whether RKIP expression is altered in clinical specimens of human primary breast cancers and their lymph node metastases.

Experimental Design: Paraffin-embedded tumor samples from 103 breast cancer patients were examined immunohistochemically for the expression of RKIP, activated ERK, and apoptosis. The specificity of the antibodies used was validated by competition experiments with purified recombinant RKIP protein.

Results: RKIP expression was high in breast duct epithelia and retained to varying degrees in primary breast tumors. However, in lymph node metastases, RKIP expression was highly significantly reduced or lost (P = 0.000003). No significant correlations were observed between RKIP expression and histologic type, tumor differentiation grade, size, or estrogen receptor status.

Conclusion: This is the first study of RKIP expression in a large clinical cohort. It confirms the results of cell culture and animal studies, suggesting that in human breast cancer, RKIP is a metastasis suppressor gene whose expression must be down-regulated for metastases to develop. RKIP expression is independent of other markers for breast cancer progression and prognosis.

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