The intermediate conductance Ca ²⁺-activated K ⁺ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors

Background and purpose: K ⁺ channels play a role in the proliferation of cancer cells. We have investigated the effects of specific K ⁺ channel inhibitors on basal and oestrogen-stimulated proliferation of breast cancer cells. Experimental approach: Using the mammary adenocarcinoma cell line MCF-7 we assayed cell proliferation by radiolabelled thymidine incorporation in the absence or presence of various K ⁺ channel inhibitors with or without 17β-oestradiol. Key results: Inhibitors of K _v10.1 and K _Ca3.1 K ⁺ channels suppressed basal proliferation of MCF-7 cells, but not oestrogen-stimulated proliferation. TRAM-34, a specific inhibitor of K _Ca3.1 channels increased or decreased cell proliferation depending on the concentration. At intermediate concentrations (3-10 μM) TRAM-34 increased cell proliferation, whereas at higher concentrations (20-100 μM) TRAM-34 decreased cell proliferation. The enhancement of cell proliferation caused by TRAM-34 was blocked by the oestrogen receptor antagonists ICI182,780 and tamoxifen. TRAM-34 also increased progesterone receptor mRNA expression, decreased oestrogen receptor-α mRNA expression and reduced the binding of radiolabelled oestrogen to MCF-7 oestrogen receptor, in each case mimicking the effects of 17β-oestradiol. Conclusions and implications: Our results demonstrate that K ⁺ channels K _v10.1 and K _Ca3.1 play a role in basal, but not oestrogen-stimulated MCF-7 cell proliferation. TRAM-34, as well as inhibiting K _Ca3.1, directly interacts with the oestrogen receptor and mimics the effects of 17β-oestradiol on MCF-7 cell proliferation and gene modulation. Our finding that TRAM-34 is able to activate the oestrogen receptor suggests a novel action of this supposedly specific K ⁺ channel inhibitor and raises concerns of interpretation in its use.