Orail is critical for Notch-driven aggressiveness under hypoxic conditions in triple-negative breast cancers

It is believed that hypoxia stimulates triple-negative breast cancers (TNBCs) metastasis, which is associated with a poor prognosis. However, the underlying mechanism remains unclear. Here, we demonstrated that hypoxia up regulates both the levels of Orai1 and Notch1, and the increase in Orai1 is mediated by Notch1 signaling in TNBCs. Functionally, Orai1 caused a sustained elevation of intracellular Ca2+ via Store-operated Case entry (SOCE), then activated the calcineurin-nuclear factor of activated T-cell 4 (NFAT4, also named NFATc3) in hypoxic TNBCs. Furthermore, pharmacologic inhibition or gene-silencing studies showed that the aggressiveness mediated by Orai1 during hypoxia is dependent on the Notch1/Orai1/SOCE/NFAT4 signaling. Moreover, Orai1 signaling also mediated hypoxia-induced angiogenesis in TNBCs. Thus, our results revealed a novel role of Orai1 as an inducer of aggression and angiogenesis under hypoxic conditions, and this suggests a novel mechanism of hypoxia-induced invasion. It may be worthwhile to further explore the potential of using Orai1 signaling as new target for anti-tumor therapy in TNBCs.