1. Calcium-sensing stromal interaction molecule 2 upregulates nuclear factor of activated T cells 1 and transforming growth factor-β signaling to promote breast cancer metastasis
- Author
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Siheng Zhang, Xiaojing Meng, Zhanxin He, Hehai Huang, Sitong Lu, Xianchong Zheng, Chunqing Cai, Qiang Shen, Zhuocheng Yao, Fei Zou, and Yutian Miao
- Subjects
Stromal cell ,Epithelial-Mesenchymal Transition ,STIM2 ,Motility ,Gene Expression ,Mice, Nude ,Breast Neoplasms ,lcsh:RC254-282 ,Metastasis ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Stromal Interaction Molecule 2 ,Cell Nucleus ,Mammary tumor ,Mice, Inbred BALB C ,NFATC Transcription Factors ,Chemistry ,EMT ,NFAT1 ,Mammary Neoplasms, Experimental ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Metastatic breast cancer ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Cancer research ,Heterografts ,Female ,Transforming growth factor ,Research Article ,Signal Transduction - Abstract
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. Electronic supplementary material The online version of this article (10.1186/s13058-019-1185-1) contains supplementary material, which is available to authorized users.
- Published
- 2019