Metastasis initiates when cancer cells escape from the primary tumor, which requires changes to intercellular junctions. Claudins are transmembrane proteins that form the tight junction, and their expression is reduced in aggressive breast tumors. However, claudins' roles during breast cancer metastasis remain unclear. We used gain- and loss-of-function genetics in organoids isolated from murine breast cancer models to establish that Cldn7 suppresses invasion and metastasis. Transcriptomic analysis revealed that Cldn7 knockdown induced smooth muscle actin (SMA)-related genes and a broader mesenchymal phenotype. We validated our results in human cell lines, fresh human tumor tissue, bulk RNA-seq, and public single-cell RNA-seq data. We consistently observed an inverse relationship between Cldn7 expression and expression of SMA-related genes. Furthermore, knockdown and overexpression of SMA-related genes demonstrated that they promote breast cancer invasion. Our data reveal that Cldn7 suppresses breast cancer invasion and metastasis through negative regulation of SMA-related and mesenchymal gene expression.

中文翻译：

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Claudin 7 通过抑制平滑肌肌动蛋白程序来抑制侵袭和转移。


当癌细胞从原发肿瘤中逃逸时，转移就开始了，这需要改变细胞间的连接。紧密连接蛋白是形成紧密连接的跨膜蛋白，其表达在侵袭性乳腺肿瘤中减少。然而，claudins 在乳腺癌转移过程中的作用仍不清楚。我们使用从小鼠乳腺癌模型中分离的类器官的功能获得和丧失遗传学来确定 Cldn7 抑制侵袭和转移。转录组分析表明，Cldn7 敲低可诱导平滑肌肌动蛋白 (SMA) 相关基因和更广泛的间充质表型。我们在人类细胞系、新鲜人类肿瘤组织、批量 RNA-seq 和公共单细胞 RNA-seq 数据中验证了我们的结果。我们一致观察到 Cldn7 表达与 SMA 相关基因表达之间呈负相关。此外，SMA 相关基因的敲除和过度表达表明它们可以促进乳腺癌侵袭。我们的数据表明，Cldn7 通过负调节 SMA 相关和间充质基因表达来抑制乳腺癌侵袭和转移。