Subunits of BK channels promote breast cancer development and modulate responses to endocrine treatment in preclinical models

Background and Purpose Pore-forming alpha subunits of the voltage- and Ca2+-activated K(+)channel with large conductance (BK alpha) promote malignant phenotypes of breast tumour cells. Auxiliary subunits such as the leucine-rich repeat containing 26 (LRRC26) protein, also termed BK gamma 1, may be required to permit activation of BK currents at a depolarized resting membrane potential that frequently occur in non-excitable tumour cells. Experimental Approach Anti-tumour effects of BK alpha loss were investigated in breast tumour-bearing MMTV-PyMT transgenic BK alpha knockout (KO) mice, primary MMTV-PyMT cell cultures, and in a syngeneic transplantation model of breast cancer derived from these cells. The therapeutic relevance of BK channels in the context of endocrine treatment was assessed in human breast cancer cell lines expressing either low (MCF-7) or high (MDA-MB-453) levels of BK alpha and BK gamma 1, as well as in BK alpha-negative MDA-MB-157. Key Results BK alpha promoted breast cancer onset and overall survival in preclinical models. Conversely, lack of BK alpha and/or knockdown of BK gamma 1 attenuated proliferation of murine and human breast cancer cells in vitro. At low concentrations, tamoxifen and its major active metabolites stimulated proliferation of BK alpha/gamma 1-positive breast cancer cells, independent of the genomic signalling controlled by the oestrogen receptor. Finally, tamoxifen increased the relative survival time of BK alpha KO but not of wild-type tumour cell recipient mice. Conclusion and Implications Breast cancer initiation, progression, and tamoxifen sensitivity depend on functional BK channels thereby providing a rationale for the future exploration of the oncogenic actions of BK channels in clinical outcomes with anti-oestrogen therapy.

Automated summary

Pore-forming alpha subunits of the BK channel play a role in promoting breast cancer, while the absence or knockdown of BK subunits attenuate the proliferation of breast cancer cells. Tamoxifen stimulates the proliferation of breast cancer cells at low concentrations.