Journal of Cellular Biochemistry

Raf Kinase Inhibitory Protein Role in the Molecular Subtyping of Breast Cancer

Authors

  • Fahd Al-Mulla,

    Corresponding author
    1. Department of Pathology, Faculty of Medicine, Kuwait University Health Sciences Centre, Safat, Kuwait
    • Correspondence to: Fahd Al-Mulla, Department of Pathology, Faculty of Medicine, Molecular Pathology Unit, Health Sciences Center, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.

      E-mail: fahd@al-mulla.org

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  • Makia Marafie,

    1. Kuwait Medical Genetics Center, Maternity Hospital, Kuwait
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  • Tuan Zea Tan,

    1. Cancer Science Institute of Singapore National University of Singapore, Center for Translational Medicine, Singapore, Singapore
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  • Jean Paul Thiery

    1. Cancer Science Institute of Singapore National University of Singapore, Center for Translational Medicine, Singapore, Singapore
    2. Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore
    3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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  • All authors have contributed in writing of this manuscript.
  • Conflict of interest: The authors have no conflict of interest except for filing a patent by the first and the last authors to the US patent office.

ABSTRACT

In this study, we examined the association between the RKIP expression and the molecular subtypes of breast cancer. Microarray gene expression data of 2,333 human breast cancer from 26 different cohorts performed on Affymetrix U133A or U133Plus2 platforms were downloaded from Array Express and Gene Expression Omnibus and the molecular subtype of breast cancer for the samples was determined by single sample Gene Set Enrichment Analysis. Differences in recurrence-free survival (RFS) were tested using the Log-rank test in univariate analysis and displayed using Kaplan–Meier curves. Cox proportional-hazards model was used to calculate the hazard ratio using univariate and multivariate analysis. Loss or reduced RKIP expression was associated with reduced RFS in breast cancer using univariate and multivariate analyses, which was independent of lymph node (LN) metastasis status. Basal-like, Claudin-low, and Her-2-enriched tumors had significantly lower RKIP levels compared to other subclasses (P < 0.0001). Conversely, the Luminal subclass exhibited the highest expression levels of RKIP (P < 0.0001 for Luminal A and P = 0.0005 for Luminal B subtype), while in normal-like breast cancer subtype, RKIP expression was not informative. RKIP expression was prognostic in ER+ and ER− subgroups. RKIP expression had no significant prognostic power within Basal-like, Claudine-low, Luminal B, or Her-2-enriched breast cancer subtypes. However, its expression pinpointed excellent from intermediate-poor Luminal A survivors, in both ER+ (P = 0.035) and ER− (P = 0.012) subgroups, especially in LN negative breast cancers. In conclusion, RKIP expression adds significant value to the molecular subclassification of breast cancer especially for the Luminal A subtype. J. Cell. Biochem. 115: 488–497, 2014. © 2013 Wiley Periodicals, Inc.

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