Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Maier, S; Schroth, W; Mier, F; Matt, L; Bischof, H; Tamaddon, A; Stojkov, D; Birkenfeld, L; Santos, MC; Gross, D; Dahlen, J; Büttner, FA; Bonzheim, I; Fend, F; Brauch, H; Boeckler, FM; Schwab, M; Lukowski, R.
Tamoxifen metabolites acting via BKCa orchestrate the dynamics of K+ and Ca2+ in breast cancer cells.
J Biol Chem. 2025; 111015
Doi: 10.1016/j.jbc.2025.111015
PubMed
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- Co-Autor*innen der Med Uni Graz
- Bischof Helmut
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- Abstract:
- 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 as of 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 intracellular 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.