STIM1 plays an important role in TGF-β-induced suppression of breast cancer cell proliferation

Store-operated calcium entry (SOCE) signaling is involved in cancer progression. Stromal interaction molecule 1 (STIM1) triggers store-operated calcium channels to induce SOCE. Transforming growth factor-beta (TGF-beta) influences a wide range of cellular behaviors, including cell proliferation. However, little is known about the relationship between calcium signaling and TGF-beta signaling in cancer cell proliferation. Here, we found that TGF-beta induced cell cycle arrest at the G0/G1 phase and suppressed cell proliferation in MDA-MB-231 and MCF-7 breast cancer cells. These effects were impaired by extracellular Ca2+ chelator EGTA or SOCE specific inhibitor SKF96365 in MDA-MB-231 cells. Treating MDA-MB-231 cells with TGF-beta for 24 and 48 h markedly decreased STIM1 expression and thapsigargin-induced SOCE. A transcriptional inhibitor of STIM1, Wilm's tumor suppressor 1 (WT1), was upregulated in TGF-beta-treated MDA-MB-231 cells, and knockdown of WT1 expression partially restored the TGF-beta-induced downregulation of STIM1. Stably overexpressing STIM1 in MDA-MB-231 cells restored the TGF-beta- induced effects. The p21 mRNA level increased in SKF96365 or TGF-beta-treated MDA-MB-231 cells, whereas that for cyclin E1 decreased. Our findings demonstrate for the first time that STIM1 and SOCE are involved in the TGF-beta-induced suppression of cell proliferation. Furthermore, our studies also provide a new approach to inhibit breast cancer cell proliferation with small molecules targeting STIM1 and SOCE.