BACKGROUND Stromal interaction molecule (STIM) 2 is a key calcium-sensing molecule that regulates the stabilization of calcium ions (Ca2+) and therefore regulates downstream Ca2+-associated signaling and cellular events. We hypothesized that STIM2 regulates epithelial-mesenchymal transition (EMT) to promote breast cancer metastasis. METHODS We determined the effects of gain, loss, and rescue of STIM2 on cellular motility, levels of EMT-related proteins, and secretion of transforming growth factor-β (TGF-β). We also conducted bioinformatics analyses and in vivo assessments of breast cancer growth and metastasis using xenograft models. RESULTS We found a significant association between STIM2 overexpression and metastatic breast cancer. STIM2 overexpression activated the nuclear factor of activated T cells 1 (NFAT1) and TGF-β signaling. Knockdown of STIM2 inhibited the motility of breast cancer cells by inhibiting EMT via specific suppression of NFAT1 and inhibited mammary tumor metastasis in mice. In contrast, STIM2 overexpression promoted metastasis. These findings were validated in human tissue arrays of 340 breast cancer samples for STIM2. CONCLUSION Taken together, our results demonstrated that STIM2 specifically regulates NFAT1, which in turn regulates the expression and secretion of TGF-β1 to promote EMT in vitro and in vivo, leading to metastasis of breast cancer.

中文翻译：

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钙敏感基质相互作用分子2上调活化T细胞1的核因子，并转化生长因子-β信号传导，促进乳腺癌的转移。

背景技术基质间相互作用分子（STIM）2是关键的钙敏感分子，其调节钙离子（Ca2 +）的稳定性，因此调节下游与Ca2 +相关的信号传导和细胞事件。我们假设STIM2调节上皮-间质转化（EMT）以促进乳腺癌转移。方法我们确定了STIM2的获得，丢失和拯救对细胞运动，EMT相关蛋白水平和转化生长因子-β（TGF-β）分泌的影响。我们还使用异种移植模型对乳腺癌的生长和转移进行了生物信息学分析和体内评估。结果我们发现STIM2过表达与转移性乳腺癌之间存在显着关联。STIM2过表达激活了活化T细胞1（NFAT1）和TGF-β信号转导的核因子。抑制STIM2可以通过特异性抑制NFAT1抑制EMT并抑制小鼠乳腺肿瘤转移，从而抑制乳腺癌细胞的运动。相反，STIM2过表达促进转移。这些发现在340个STIM2乳腺癌样品的人体组织阵列中得到了验证。结论综上所述，我们的结果表明STIM2特异性调节NFAT1，进而调节TGF-β1的表达和分泌，以在体内和体外促进EMT，从而导致乳腺癌的转移。