We found an inverse association between KCNMA1 amplification and AR expression. Almost all KCNMA1 amplified, but only 11 of 25 non-amplified breast cancers were AR-negative. The role of AR in breast cancer has not yet been fully elucidated, but it has been postulated that AR has an anti-proliferative and favourable prognostic effect in ER-positive breast cancer, whereas it has a growth-stimulating and unfavourable prognostic effect in ER-negative breast cancer. It has previously been demonstrated that not only 17b-estradiol but also testosterone can relax smooth muscle by potentiating BK channels. Responsiveness to these sex hormones could explain why BK channel up-regulation and KCNMA1 amplification occur in hormone-regulated cancers. Further studies are needed to elucidate the complex interplay between sex hormones and KCNMA1 in breast- and prostate cancer that is likely to be influenced by the type of regulatory ß-subunits of the BK channel, alternative splicing, the background of ER and/or AR status, and anti-hormone therapy. Unfortunately, there is currently no reliable antibody for formalin-fixed and paraffin-embedded material. Therefore, we could not test the prevalence and significance of KCNMA1 protein expression in a large number of clinical cancer specimens. Proton fluxes across membranes are of crucial importance for cell functioning. The mostly studied are active fluxes through proton pumps of electron transfer chains providing proton motive force as an energetic intermediate between oxidation and ATP synthesis, in other words, underlying the energetic coupling of electron transfer and phosphorylation in mitochondria, chloroplasts and bacteria. Of the key importance for cellular physiology is also the functioning of proton pumps in endosomes resulting in acidification of their interior which is a prerequisite of their maturation and intracellular traffic. In plasma membranes of eukaryotic cells, proton pumps also play a significant role, e.g. providing intragastric acidification. Another type of passive transmembrane proton fluxes is found in proton channels of plasma membranes which determine such vital processes as immune responses of certain kinds of blood cells. A breakthrough in uncovering the mechanism of oxidative phosphorylation in mitochondria was promoted by the early observations that some aromatic weak acids are able to selectively transfer protons across artificial and natural membranes thereby leading to uncoupling of electron transfer and phosphorylation. The capability of uncoupling was also found to be characteristic of a new class of membrane proteins, the so-called uncoupling proteins, which appeared to cause a reduction of the mitochondrial membrane potential in the presence of fatty acids. To this end, it is of importance that a high magnitude of the mitochondrial membrane potential could be harmful for cells through generation of excess of reactive oxygen species provoking a series of pathological processes in tissues. By contrast, a moderate decrease in membrane potential was shown to protect cells from oxidative damage. Thus, protonophores represent potential drugs. Actually in 1930-s 2,4-dinitrophenol was used as a drug against obesity. However, later it was prohibited due to high toxicity. NSC 136476 Hedgehog inhibitor Cytotoxicity of uncouplers is generally attributed to an excessive increase in proton conductivity of the inner mitochondrial membrane, although ionic balance across other cellular membranes can be also changed by uncouplers. Reduction of the toxicity might be associated with voltage dependence of their action, e.g. a drop in activity upon partial depolarization of the inner mitochondrial membrane, which may prevent an uncontrolled decrease in ATP synthesis and cell death.