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
Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Germany.
Br J Pharmacol. 2022 Jun;179(12):2906-2924. doi: 10.1111/bph.15147. Epub 2020 Aug 27.
Pore-forming α subunits of the voltage- and Ca -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.
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.
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.
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.
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.
大电导电压和钙激活钾通道的成孔α亚基（BKα）可促进乳腺肿瘤细胞的恶性表型。辅助亚基，如富含亮氨酸重复序列26（LRRC26）蛋白，也称为BKγ1，可能是使非兴奋性肿瘤细胞中常见的去极化静息膜电位下BK电流得以激活所必需的。
在携带乳腺肿瘤的MMTV-PyMT转基因BKα基因敲除（KO）小鼠、原代MMTV-PyMT细胞培养物以及源自这些细胞的乳腺癌同基因移植模型中，研究BKα缺失的抗肿瘤作用。在表达低水平（MCF-7）或高水平（MDA-MB-453）BKα和BKγ1的人乳腺癌细胞系以及BKα阴性的MDA-MB-157细胞系中，评估BK通道在内分泌治疗背景下的治疗相关性。
在临床前模型中，BKα促进乳腺癌的发生和总体生存期。相反，BKα的缺失和/或BKγ1的敲低可减弱小鼠和人乳腺癌细胞在体外的增殖。在低浓度下，他莫昔芬及其主要活性代谢物可刺激BKα/γ1阳性乳腺癌细胞的增殖，这与雌激素受体控制的基因组信号无关。最后，他莫昔芬增加了BKα基因敲除小鼠而非野生型肿瘤细胞受体小鼠的相对存活时间。
乳腺癌的发生、进展以及对他莫昔芬的敏感性取决于功能性BK通道，从而为未来探索BK通道在抗雌激素治疗临床结果中的致癌作用提供了理论依据。
本文是关于癌症预防与治疗新途径（《英国药理学杂志》75周年）主题系列的一部分。要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc。
