LAUSR

eBioMedicine 2022;76: 103853 Published online xxx https://doi.org/10.1016/j. ebiom.2022.103853 Cell membrane potential (Em) is essential for electrical activities in excitable cells such as neurons and heart cells. Accumulating data has now revealed an important role of Em in non-excitable cells such as epithelial cells. Alterations in Em (depolarization Em becoming more positive, or hyperpolarization Em becoming more negative) play a crucial role in controlling cell cycles. In breast cancer biopsy independent of estrogen receptor (ER) or progesterone receptor (PR) presence, Em was found to be -13 mV, significantly depolarized as compared to Em (about -60 mV) in normal breast cells. Depolarization has been proposed as a biomarker for breast cancer. Membrane depolarization activates ion channels that are linked to hallmarks of cancer, such as initiation, invasion, and metastasis. Voltage-gated sodium channels (VGSCs) have been demonstrated to contribute to breast cancer metastasis. Depolarization-triggered electrical excitability has now been observed in metastatic breast cancer cells. In a recent issue of EBioMedicine, Payne et al. presented strong evidence for a novel hyperpolarizationdriven metastasis in breast cancer cells in vitro and in vivo. The authors demonstrated that in triple-negative breast cancer (TNBC) patients K channels are overexpressed, while Na and Cl channels are not, compared to PR/ER and HER2 patients; overexpressing Kv1.5 or Kir2.1 in metastasis cell lines, MDA-MB-231 and MDA-MB-468, resulted in a significant membrane hyperpolarization associated with an enhanced invasion in vitro and metastasis in vivo; hyperpolarization caused changes in cell morphology, focal adhesion signaling required for cell migration and invasion, and increased the expression of genes associated with cell adhesion and MAPK signaling. They identified cadherin-11 as the key protein that drives migration induced by hyperpolarization; the authors proposed the use of FDAapproved K channel blockers to inhibit TNBC metastasis. They illustrated this idea by showing that an antiarrhythmic drug, amiodarone, can depolarize TNBC cell