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 (BKCa) 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 BKCa status. However, the mechanism by which TAM+M impact on BKCa 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 BKCa-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 BKCa significantly diminished the TAM+M-induced modulation of BKCa 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-BKCa axis. Our results highlight that BKCa "oncochannels" may modulate the response of BC cells to TAM+M. Activation of the TAM+M-BKCa axis causes significant changes in K+ and Ca2+ ion homeostasis, which ultimately contributes to the outcome of endocrine-based BC pharmacotherapy.