The intermediate conductance Ca2+-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 17beta-oestradiol.

Key results: Inhibitors of K(v)10.1 and K(CA)3.1 K(+) channels suppressed basal proliferation of MCF-7 cells, but not oestrogen-stimulated proliferation. TRAM-34, a specific inhibitor of K(CA)3.1 channels increased or decreased cell proliferation depending on the concentration. At intermediate concentrations (3-10 microM) TRAM-34 increased cell proliferation, whereas at higher concentrations (20-100 microM) 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-alpha mRNA expression and reduced the binding of radiolabelled oestrogen to MCF-7 oestrogen receptor, in each case mimicking the effects of 17beta-oestradiol.

Conclusions and implications: Our results demonstrate that K(+) channels K(v)10.1 and K(CA)3.1 play a role in basal, but not oestrogen-stimulated MCF-7 cell proliferation. TRAM-34, as well as inhibiting K(CA)3.1, directly interacts with the oestrogen receptor and mimics the effects of 17beta-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.