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

• Published in: British journal of pharmacology Vol. 179; no. 12; pp. 2906 - 2924
• Main Authors: Mohr, Corinna J., Schroth, Werner, Mürdter, Thomas E., Gross, Dominic, Maier, Selina, Stegen, Benjamin, Dragoi, Alice, Steudel, Friederike A., Stehling, Severine, Hoppe, Reiner, Madden, Stephen, Ruth, Peter, Huber, Stephan M., Brauch, Hiltrud, Lukowski, Robert
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-06-2022
• Subjects: Animals; Antiestrogens; Breast cancer; Breast Neoplasms - drug therapy; Calcium channels (voltage-gated); Cell proliferation; estrogen receptor; Female; Humans; Large-Conductance Calcium-Activated Potassium Channels; leucine‐rich repeat 49 containing 26; Membrane potential; Membrane Potentials; Mice; Mice, Knockout; Mice, Transgenic; mouse mammary tumour virus polyoma middle T antigen; Phenotypes; Potassium channels (calcium-gated); Potassium channels (voltage-gated); Potassium conductance; selective Estrogen Receptor Modulator 51; Tamoxifen; Tamoxifen - pharmacology; Transgenic mice; Transplantation; Tumor cell lines; Tumors; Voltage‐ and Ca2+‐activated K+ channels of big conductance; mouse mammary tumour virus polyoma middle T antigen; estrogen receptor; leucine-rich repeat 49 containing 26; breast cancer; selective Estrogen Receptor Modulator 51; Voltage- and Ca2+-activated K+ channels of big conductance; tamoxifen
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.15147

Background and Purpose
Pore‐forming α subunits of the voltage‐ and Ca2+‐activated K+ channel with large 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 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 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 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 BKα and BKγ1, as well as in BKα‐negative MDA‐MB‐157.
Key Results
BKα promoted breast cancer onset and overall survival in preclinical models. Conversely, lack of BKα and/or knockdown of BKγ1 attenuated proliferation of murine and human breast cancer cells in vitro. At low concentrations, tamoxifen and its major active metabolites stimulated proliferation of BKα/γ1‐positive breast cancer cells, independent of the genomic signalling controlled by the oestrogen receptor. Finally, tamoxifen increased the relative survival time of BKα 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.
LINKED ARTICLES
This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc