Tamoxifen metabolites acting via BKCa orchestrate the dynamics of K+ and Ca2+ in breast cancer cells

The voltage- and calcium (Ca²⁺)-activated potassium (K⁺) channel of large conductance (BK_Ca) is aberrantly expressed in various breast cancer (BC) subtypes, including estrogen receptor (ER)-positive tumors. Increased proliferation of BC cells in response to tamoxifen (TAM) and its metabolites (TAM+M) has been shown to rely on the cell's BK_Ca status. However, the mechanism by which TAM+M impact on BK_Ca activity to promote malignancy is yet not clear. By examining murine MMTV-PyMT tumor-derived BC cells and human BC cell lines with a genetically encoded K⁺ ion indicator and electrophysiological recordings, we identified BK_Ca-dependent intracellular K⁺ signals and currents provoked by treatment with clinically relevant TAM+M in an ER-independent manner. In line with this, genetical or pharmacological blockade of BK_Ca significantly diminished the TAM+M-induced modulation of BK_Ca K⁺ currents and consequently also the drop of intracellular K⁺ ions in BC cells. Changes in the K⁺ balance subsequently triggered intra- and extracellular Ca²⁺ mobilization, which was in turn stimulated by the TAM+M-BK_Ca axis. Our results highlight that BK_Ca "oncochannels" may modulate the response of BC cells to TAM+M. Activation of the TAM+M-BK_Ca axis causes significant changes in K⁺ and Ca²⁺ ion homeostasis, which ultimately contributes to the outcome of endocrine-based BC pharmacotherapy.