The progression of triple-negative breast cancer is linked to a gradual decrease of the BK channel in the plasma membrane and an increase in intracellular structures.

Abstract

Big Potassium (BK) channels are gated by both the membrane potential and intracellular Ca^2+, and hence they have multiple physiological roles, from canonical control of cellular excitability to modulate cell metabolism, proliferation, and gene expression. Growing evidence implicates BK channels in several oncogenic processes, including breast cancer. Though, the role of these channels in the deleterious triple-negative breast cancer (TNBC) is unknown. In this study, electrophysiological methods and immunocytochemistry were performed to assess the functional contribution of BK channels in the progression of TNBC, using cell lines of increasing tumor stages. Firstly, we unveiled that BK channel is the main contributor of K⁺ outward current in non-tumoral mammary cells (MCF-10 A and MCF-12 A). Also, as the cancer stage increased, the BK current density decreased (which was consistent with the lower expression of BK protein in the plasma membrane), whereas the protein was overexpressed inside tumoral cells. Biological assays disclose that pharmacological inhibition of BK channels in non-tumoral and TNBC cells enhanced cell migration, proliferation, and viability. Overall, these channels appear to have opposite role at the plasma membrane and intracellularly, since both the reduction of BK channel activity at the plasma membrane (either by decreased expression or by paxilline blockade) and the increased intracellular expression of this protein favor TNBC malignancy. Our findings suggest that BK channels may have multiple physiological implications in TNBC, depending on their function and the cellular organelle in which they are expressed.