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Voltage-Gated Sodium Channel Expression and Potentiation of Human Breast Cancer Metastasis

Authors' Affiliations: ¹ Neuroscience Solutions to Cancer Research Group, Department of Biological Sciences, Imperial College London; ² Medical Molecular Biology Unit, Institute of Child Health, University College; ³ Department of Cancer Medicine, CRC Laboratories, Medical Research Council Cyclotron Building, Imperial College School of Medicine, London, United Kingdom; ⁴ Department of Molecular Biology and Genetics, Bogazici University; ⁵ Department of Histology and Embryology, Kadir Has University; ⁶ Department of Pathology, Marmara University, Medical School, Istanbul, Turkey; and ⁷ Department of Physical Chemistry and Technology of Polymers, Silesian Technical University, Gliwice, Poland

Requests for reprints: Mustafa B.A. Djamgoz, Department of Biological Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, United Kingdom. Phone: 20-7594-54370; Fax: 20-7584-2056; E-mail: m.djamgoz{at}imperial.ac.uk.

Purpose: Ion channel activity is involved in several basic cellular behaviors that are integral to metastasis (e.g., proliferation, motility, secretion, and invasion), although their contribution to cancer progression has largely been ignored. The purpose of this study was to investigate voltage-gated Na⁺ channel (VGSC) expression and its possible role in human breast cancer.

Experimental Design: Functional VGSC expression was investigated in human breast cancer cell lines by patch clamp recording. The contribution of VGSC activity to directional motility, endocytosis, and invasion was evaluated by in vitro assays. Subsequent identification of the VGSC -subunit(s) expressed in vitro was achieved using reverse transcription-PCR, immunocytochemistry, and Western blot techniques and used to investigate VGSC expression and its association with metastasis in vivo.

Results: VGSC expression was significantly up-regulated in metastatic human breast cancer cells and tissues, and VGSC activity potentiated cellular directional motility, endocytosis, and invasion. Reverse transcription-PCR revealed that Na_v1.5, in its newly identified "neonatal" splice form, was specifically associated with strong metastatic potential in vitro and breast cancer progression in vivo. An antibody specific for this form confirmed up-regulation of neonatal Na_v1.5 protein in breast cancer cells and tissues. Furthermore, a strong correlation was found between neonatal Na_v1.5 expression and clinically assessed lymph node metastasis.

Conclusions: Up-regulation of neonatal Na_v1.5 occurs as an integral part of the metastatic process in human breast cancer and could serve both as a novel marker of the metastatic phenotype and a therapeutic target.

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