Breast cancer is the most frequent form of cancer in women and the second causing-death cancer after lung cancer [1]. Cancer results from a deregulation between cell proliferation and cell death. Alterations in both calcium homeostasis and ion channels have been reported to play a role in mammary gland physiopathology [2]. Calcium channels were shown to be involved in breast cancer proliferation [3]. Orai proteins form calcium channels able to mediate store operated calcium entry (SOCE) upon endoplasmic reticulum calcium depletion. Studies from our laboratory demonstrated that Orai3 channels were overexpressed in breast cancer biopsies, and Orai3 downregulation impacted proliferation, cell cycle progression and survival of breast cancer cells. These effects are specific to cancer cells, since down-regulation of Orai3 channels does not affect either cell proliferation or cell survival of normal breast cells [4].In this context, we wondered whether Orai3 overexpression could affect proliferation and survival of breast cancer cells. Clones of the T47D breast cancer cell line stably overexpressing Orai3 were created. Orai3 overexpression was confirmed both at the mRNA and protein levels. Functionality was assessed by Ca2+ imaging using 2-APB, an Orai3 channel activator when used at 50 μM. Only Orai3 overexpressing cells displayed calcium entry upon 2-APB application. Orai3 overexpression affects cell mortality but not cell proliferation, as shown in trypan blue assay and flow cytometry. Cells overexpressing Orai3 showed indeed lower mortality percentages than the control cells in normal conditions, after serum deprivation or after treatment with thapsigargin (which inhibits SERCA pumps, thus depleting internal calcium stores of the endoplasmic reticulum, and usually induces death). In order to determine whether the resistance to death conferred by Orai3 is due to Ca2+ influx, cells were treated with thapsigargin (to activate SOCE) in the presence and in the absence of extracellular Ca2+. Our results show that cells overexpressing Orai3 lose resistance to cell death when extracellular Ca2+ is lacking. To identify the mechanism by which Orai3 channels confer death resistance to breast cancer cells, we explored the PI3K/Akt survival signaling pathway. Treatment of cells overexpressing Orai3 with LY294002, a PI3K specific inhibitor, completely abolished the resistance to thapsigargin death conferred by Orai3.In conclusion, we demonstrate that Orai3 calcium channels confer resistance to breast cancer cells against cell death. This resistance depends on extracellular Ca2+ and is mediated, at least in part, by the PI3K/Akt signaling pathway. Taken together, our findings suggest that Orai3 channel could be an anti-apoptotic factor. Interestingly, Orai1 was on the contrary found to be a pro-apoptotic factor [5].