The intermediate conductance Ca ⁺ 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.