TRAM‐34 stimulates the proliferation of breast cancer cells via activation of estrogen receptors

We have investigated the effects of specific K + channel inhibitors on basal and estrogen (E2)‐stimulated proliferation of breast cancer cells. Using the mammary adenocarcinoma cell line MCF‐7 we assayed cell proliferation by [ 3 H]‐thymidine incorporation in the absence or presence of various K + channel inhibitors with or without E2. Inhibitors of hEAG and hIK K + channels inhibited basal, but not E2‐stimulated proliferation of MCF‐7 cells. TRAM‐34, a specific inhibitor of hIK channels increased cell proliferation at intermediate concentrations (3‐10 µM), whereas at higher concentrations (20‐30 µM) TRAM‐34 decreased cell proliferation. The mitogenic effect of TRAM‐34 was blocked by the estrogen receptor antagonist ICI182,780. TRAM‐34 also (i) increased progesterone receptor mRNA expression, (ii) decreased estrogen receptor‐α mRNA expression, and (iii) reduced the binding of radiolabelled E2 to MCF‐7 estrogen receptor protein, in each case mimicking the effects of E2. Our results demonstrate that K + channels hEAG and hIK play a role in basal, but not E2‐stimulated MCF‐7 cell proliferation. TRAM‐34, as well as inhibiting hIK, interacts directly with the estrogen receptor and mimics the effects of E2 on MCF‐7 cell proliferation and gene expression. Our finding that TRAM‐34 may be able to activate the estrogen receptor suggests a novel action of this supposedly specific K + channel inhibitor. (NSHRF, CBCF)