Oestrogen is well known to be involved in development and progression of human breast cancer (BCa) but problems remain in understanding its modes of action and maximizing its therapeutic potential (Ali & Coombes, 2002). We have shown (i) that a voltage-gated sodium channel (VGSC), Nav1.5, in its newly identified neonatal splice form (nNav1.5) is selectively upregulated in both the human metastatic BCa cell line MDA-MB-231 and biopsy tissues and (ii) that VGSC activity enhances metastatic cell behaviours (Fraser et al. 2005). Thus, oestrogen signalling and VGSC expression/activity could be functionally associated. Oestrogen classically works as a transcriptional regulator through α and β oestrogen receptors (ERs). We have investigated whether oestrogen signalling could affect VGSC expression/activity. All experiments were carried out over 48-72 h on MDA-MB-231 cells transfected with ERα. The cells were cultured as described before (Fraser et al. 2005). Data are presented as mean ± SEM. Statistical significance was determined by either unpaired t test or chi-squared test, as appropriate. Real-time PCR showed that treatment with the pure ER antagonist ICI-182,780 (1 μM) for 72 h significantly increased Nav1.5 mRNA levels by 211 ± 47% (n=4). Whole-cell patch clamp recordings revealed that similar treatment over >48 h increased the proportion of cells expressing functional VGSCs. Thus, the proportion of VGSC-expressing cells rose significantly from 21 to 65% (n=73; χ² = 12.3; df = 1; p < 0.001). There was no change in peak current density. As regards functional consequence, a 72 h pretreatment with ICI-182,780 significantly increased the cells' transverse migration by 32 ± 13% (p = 0.01; n = 8). The latter was determined by ‘transwell’ assays over 7 h which would exclude any proliferative effect. In conclusion, under the experimental conditions used, estrogen downregulated VGSC expression and functional activity. These observations were consistent with the effect on the cells' migratory potential. Thus, for the particular cell line studied, we propose the following working hypothesis: Oestrogen → VGSC downregulation → reduced metastatic cell behaviour.