Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Breast Cancer Res Treat. 2021 May;187(1):31-43. doi: 10.1007/s10549-021-06133-7. Epub 2021 Feb 25.
Breast cancer is the most common cancer affecting women worldwide with half a million associated deaths annually. Despite a huge global effort, the pathways of breast cancer progression are not fully elucidated. Ion channels have recently emerged as novel regulators of cancer cell proliferation and metastasis. The epithelial sodium channel, ENaC, made up of α, β and γ subunits is well known for its role in Na reabsorption in epithelia, but a number of novel roles for ENaC have been described, including potential roles in cancer. A role for ENaC in breast cancer, however, has yet to be described. Therefore, the effects of ENaC level and activity on breast cancer proliferation were investigated.
Through the publicly available SCAN-B dataset associations between αENaC mRNA expression and breast cancer subtypes, proliferation markers and epithelial-mesenchymal transition markers (EMT) were assessed. αENaC expression, through overexpression or siRNA-mediated knockdown, and activity, through the ENaC-specific inhibitor amiloride, were altered in MCF7, T47D, BT549, and MDAMB231 breast cancer cells. MTT and EdU cell proliferation assays were used to determine the effect of these manipulations on breast cancer cell proliferation.
High αENaC mRNA expression was associated with less aggressive and less proliferative breast cancer subtypes and with reduced expression of proliferation markers. Decreased αENaC expression or activity, in the mesenchymal breast cancer cell lines BT549 and MDAMB231, increased breast cancer cell proliferation. Conversely, increased αENaC expression decreased breast cancer cell proliferation.
αENaC expression is associated with a poor prognosis in breast cancer and is a novel regulator of breast cancer cell proliferation. Taken together, these results identify ENaC as a potential future therapeutic target.
乳腺癌是全球女性最常见的癌症，每年有 50 万人因此死亡。尽管全球做出了巨大努力，但乳腺癌的发展途径仍未完全阐明。离子通道最近成为癌细胞增殖和转移的新型调节剂。由α、β和γ亚基组成的上皮钠通道（ENaC）以其在上皮细胞中钠重吸收的作用而闻名，但 ENaC 的许多新作用已被描述，包括在癌症中的潜在作用。然而，ENaC 在乳腺癌中的作用尚未被描述。因此，研究了 ENaC 水平和活性对乳腺癌增殖的影响。
通过公开的 SCAN-B 数据集，评估了αENaC mRNA 表达与乳腺癌亚型、增殖标志物和上皮-间充质转化标志物（EMT）之间的相关性。通过过表达或 siRNA 介导的敲低改变 MCF7、T47D、BT549 和 MDAMB231 乳腺癌细胞中的αENaC 表达，通过 ENaC 特异性抑制剂阿米洛利改变 ENaC 活性。MTT 和 EdU 细胞增殖测定用于确定这些操作对乳腺癌细胞增殖的影响。
高αENaC mRNA 表达与侵袭性较低和增殖性较低的乳腺癌亚型相关，与增殖标志物的表达降低相关。在间充质乳腺癌细胞系 BT549 和 MDAMB231 中，降低αENaC 表达或活性会增加乳腺癌细胞增殖。相反，增加αENaC 表达会降低乳腺癌细胞增殖。
αENaC 表达与乳腺癌的不良预后相关，是乳腺癌细胞增殖的新型调节剂。综上所述，这些结果表明 ENaC 是未来潜在的治疗靶点。
