We have shown previously that functional voltage-gated Na⁺ channels (VGSCs) were expressed specifically in strongly metastatic rat and human prostate cancer (PCa) cell lines (Grimes et al. 1995; Laniado et al. 1997). This VGSC was tetrodotoxin (TTX) sensitive, Nav1.7 being the predominant subtype expressed (Diss et al. 2001). Furthermore, blocking VGSC activity in these cells suppressed a variety of cellular behaviours involved in the metsatatic cascade, such as basic and galvanotactic motility (Fraser et al. 1998; Djamgoz et al. 2001), endocytic membrane activity (Mycielska et al. 2001) and Matrigel invasion (Grimes et al. 1995; Laniado et al. 1997). In the present study, we have investigated whether a similar situation may exist in breast cancer (BCa) cell lines of markedly different metastatic ability.

Whole-cell patch clamp recordings were obtained from MCF-10A, MCF-7 and MDA-MB-231 cells cultured in RPMI 1640 medium with 10 % fetal bovine serum. Voltage-gated currents were activated by applying depolarizing pulses in steps of 10 mV from a holding potential of -100 mV. The basic electrophysiological observations are summarised in Table 1. In essence, an inward current was present in 29 % (n = 56) of the strongly metastatic MDA-MB-231cells, but in none of the other cell lines tested. On the other hand, outward current density was inversely related to the cells’ metastatic ability, such that only very small outward currents were recorded in the MDA-MB-231cells. The inward currents were blocked by TTX in a dose-dependent fashion, the IC₅₀ being greater than 1 µM, i.e. the VGSC was TTX-resistant. Indeed, semi-quantitative RT-PCR analyses revealed that Nav1.5 was the predominant VGSC expressed in this cell line. The possible role of VGSC activity in metastasis was tested in Matrigel invasion experiments (Boyden chambers with chemo-attractant). These functional assays showed that pre-treating cells with 10 µM TTX reduced their invasiveness by some 40 %.

In conclusion: (1) Strongly metastatic BCa cells are potentially electrically excitable and (2) VGSC activity could accelerate metastasis in BCa, as found previously for PCa cells.

This work was supported by Cancer Research UK and the Pro Cancer Research Fund.