Unlike other breast cancer subtypes that may be treated with a variety of hormonal or targeted therapies, there is a need to identify new, effective targets for triple-negative breast cancer (TNBC). It has recently been recognized that membrane potential is depolarized in breast cancer cells. The primary objective of the study is to explore whether hyperpolarization induced by opening potassium channels may provide a new strategy for treatment of TNBC. Breast cancer datasets in cBioPortal for cancer genomics was used to search for ion channel gene expression. Immunoblots and immunohistochemistry were used for protein expression in culture cells and in the patient tissues. Electrophysiological patch clamp techniques were used to study properties of BK channels in culture cells. Flow cytometry and fluorescence microscope were used for cell viability and cell cycle studies. Ultrasound imaging was used to study xenograft in female NSG mice. In large datasets of breast cancer patients, we identified a gene, KCNMA1 (encoding for a voltage- and calcium-dependent large-conductance potassium channel, called BK channel), overexpressed in triple-negative breast cancer patients. Although overexpressed, 99% of channels are closed in TNBC cells. Opening BK channels hyperpolarized membrane potential, which induced cell cycle arrest in G2 phase and apoptosis via caspase-3 activation. In a TNBC cell induced xenograft model, treatment with a BK channel opener significantly slowed tumor growth without cardiac toxicity. Our results support the idea that hyperpolarization induced by opening BK channel in TNBC cells can become a new strategy for development of a targeted therapy in TNBC.

中文翻译：

---

打开大电导钾通道选择性诱导三阴性乳腺癌的细胞死亡。

与可以使用多种激素或靶向疗法治疗的其他乳腺癌亚型不同，需要确定三阴性乳腺癌（TNBC）的新有效靶标。最近已经认识到，在乳腺癌细胞中膜电位被去极化。该研究的主要目的是探讨开放钾离子通道诱导的超极化是否可能为TNBC的治疗提供新的策略。使用cBioPortal中用于癌症基因组学的乳腺癌数据集来搜索离子通道基因表达。免疫印迹和免疫组织化学用于培养细胞和患者组织中的蛋白质表达。电生理膜片钳技术用于研究培养细胞中BK通道的特性。流式细胞仪和荧光显微镜用于细胞活力和细胞周期研究。超声成像用于研究雌性NSG小鼠的异种移植。在乳腺癌患者的大型数据集中，我们确定了在三阴性乳腺癌患者中过表达的基因KCNMA1（编码依赖电压和钙的大电导钾通道，称为BK通道）。尽管过表达，但TNBC细胞中99％的通道是封闭的。开放的BK通道超极化的膜电位，其诱导细胞周期停滞在G2期并通过caspase-3激活引起凋亡。在TNBC细胞诱导的异种移植模型中，用BK通道开放剂治疗可显着减慢肿瘤生长而无心脏毒性。