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

• Published in: Clinical cancer research Vol. 11; no. 20; pp. 7392 - 7397
• Main Authors: Suzanne Hagan, Fahd Al-Mulla, Elizabeth Mallon, Karin Oien, Rhona Ferrier, Barry Gusterson, Jorge J. Curto García, Walter Kolch
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2005
• Subjects: Androgen-Binding Protein - biosynthesis; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cohort Studies; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; lymph node; Lymphatic Metastasis; Mammary gland diseases; Medical sciences; metastasis; Phosphatidylethanolamine Binding Protein; Phosphorylation; Raf kinase inhibitor protein; Tumors; Mammary gland diseases; Protein inhibitor; Enzyme; Protein kinase; Transferases; Breast cancer; Malignant tumor; Metastasis; Gene expression
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0283

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.