Background and purpose: Pore-forming α subunits of the voltage- and Ca2+ -activated K+ channel of big conductance (BKα) promote malignant phenotypes of breast tumour cells. Auxiliary subunits such as the leucine-rich repeat containing 26 (LRRC26) protein, also termed BKγ1, may be required to confer activation of BK currents at a depolarized resting membrane potential that frequently occur in an inexcitable tumour cell.
Experimental approach: Anti-tumour effects of BKα loss were investigated in breast tumour-bearing MMTV-PyMT transgenic BKα knockout (KO) mice, primary MMTV-PyMT cell cultures, and in a syngeneic transplantation model of breast cancer (BC) derived thereof. The therapeutic relevance of BK channels in the context of endocrine treatment was assessed in human BC cell lines expressing either low (MCF-7) or high (MDA-MB-453) levels of BKα and BKγ1, as well as BKα-negative MDA-MB-157.
Key results: BKα promoted BC onset and overall survival in pre-clinical models. Conversely, lack of BKα and/or knockdown of BKγ1 attenuated the proliferation of murine and human BC cells in vitro. At low concentrations, tamoxifen (TAM) and its major active metabolites stimulated proliferation of BKα/γ1-positive BC cells, an effect that occurred independently from the genomic signalling controlled by the estrogen receptor. Finally, TAM increased the relative survival time of BKα KO but not of wildtype tumour cell recipient mice.
Conclusion and implications: BC initiation, progression and TAM sensitivity depend on functional BK channels thereby providing a rationale for the future exploration of BK’s oncogenic actions in clinical outcomes with anti-estrogen therapy.