Orai2 Modulates Store-Operated Ca(2+) Entry and Cell Cycle Progression in Breast Cancer Cells

SIMPLE SUMMARY: Breast cancer shows a high heterogeneity which accounts for cancer subtype aggressiveness. Store-operated calcium entry (SOCE) is significantly remodeled in breast cancer cells and supports a variety of cancer hallmarks. Here we show that breast cancer cells from different subtypes exhibit a variable Orai1:Orai2 expression ratio. In cells with a high Orai2 expression, Orai2 modulates the magnitude SOCE and support Ca(2+) oscillations in response to agonists, thus modulating the activation of the transcription factors NFAT1 and NFAT4. Furthermore, Orai2 plays a relevant role in cell cycle progression and apoptosis resistance. ABSTRACT: Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca(2+) entry (SOCE), a major mechanism for Ca(2+) entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca(2+) release-activated Ca(2+)) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca(2+) responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca(2+) oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca(2+) signals, cell proliferation and apoptosis resistance.