mitoBK_Cais functionally expressed in murine and human breast cancer cells and promotes metabolic reprogramming

Alterations in the function of K⁺channels such as the voltage- and Ca²⁺activated K⁺channel of large conductance (BK_Ca) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BK_Casplice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBK_Ca). Through a combination of genetic knockdown and knockout along with cell permeable BK_Cachannel blocker, we show that mitoBK_Camodulates overall cellular and mitochondrial energy production and mediates the metabolic rewiring referred to as the “Warburg effect”, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBK_Caand BK_Catranscripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBK_Ca, combined with established anti-cancer approaches, could represent a novel treatment strategy for selected BC patients.