The antiestrogen tamoxifen activates BK channels and stimulates proliferation of MCF-7 breast cancer cells

In the present study, we investigated the effect of the antiestrogen compound tamoxifen on BK channels by the use of the patch-clamp technique. The perfusion of 10 nM tamoxifen significantly increased the magnitude of a voltage-dependent K+ current by 22.6 +/- 10.6% (n=23). The effect of tamoxifen was always obtained in the first minute, peaked at 5.9 +/- 2.2 min (n=23), and was abolished by the perfusion of tetraethylammonium (0.5 mM), charybdotoxin ( 50 nM), or iberiotoxin ( 100 nM). The stimulatory effect of 10 nM tamoxifen was the same at low ( 50 nM) and high ( 700 nM) internal calcium concentration and was not additive to that of 17-beta-estradiol (E-2) or its membrane-impermeant form, beta-estradiol 6-(O-carboxymethyl)-oxime: bovine serum albumin. Furthermore, the effect of tamoxifen was still recorded in the presence of the selective estrogen receptor antagonist faslodex (ICI-182,780; 1 mu M). At the single-channel level, tamoxifen significantly increased the open probability of the BK channel by 46.2 +/- 10.1% (n=4) without changing its unitary conductance. Moreover, we show here that the stimulation of BK channel activity by tamoxifen is involved in MCF-7 cell proliferation. Taken together, these results permitted us to identify the BK channel as the molecular target of tamoxifen that probably acts at the same extracellular molecular level as E-2. The site of action of tamoxifen is probably the channel itself or the auxiliary beta subunits.