Basic studies on TOPK as a target molecule of cancer

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Purpose: A MAPKK-like mitotic protein kinase, TOPK, plays a pivotal role in the growth and movement of cancer cells. As is evidenced by clinical application of anti-HER2-monoclonal antibody, EGF-R/HER2 mediates an important signaling in the proliferation and invasion of breast cancer cells through MAPK- and PI3K- signaling. Raf, an imperative member of MAPK signaling, binds to TOPK, although, significance of this interaction has not been elucidated. In this study, we analyzed expression of TOPK and investigated biological significance of TOPK-Raf interaction using breast cancer cells.Experimental Design: We analyzed the expression of TOPK in the clinical breast cancer tissues and investigated MAPK-signaling from the aspect of TOPK and Raf in breast cancer cells.Results: Immunohistochemical analysis revealed that the peak-expression intensity of TOPK correlated with the Histologic Grade of human invasive ductal carcinoma of breast. Our results suggested that Raf phosphorylates TOPK at Thr-198, a critical residue for kinase activity of TOPK and that TOPK enhances MAPK signaling by upregulating Ras binding to Raf.Conclusions: TOPK is indicated to play an important role in the malignant potential of breast cancer via EGF-R/HER2 signaling. This study suggests that TOPK can be a molecular target for breast cancer therapy in the future.