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Background Stromal interaction molecule (STIM) 2 is a key calcium-sensing molecule that regulates the stabilization of calcium ions (Ca 2+ ) and therefore regulates downstream Ca 2+ -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. Electronic supplementary material The online version of this article (10.1186/s13058-019-1185-1) contains supplementary material, which is available to authorized users.

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