NCS-1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin.

Neuronal calcium sensor-1 (NCS-1) is a positive modulator of IP₃ receptors and was recently associated with poorer survival in breast cancers. However, the association between NCS-1 and breast cancer molecular subtypes and the effects of NCS-1 silencing on calcium (Ca²⁺ ) signaling in breast cancer cells remain unexplored. Herein, we report for the first time an increased expression of NCS-1 in breast cancers of the basal molecular subtype, a subtype associated with poor prognosis. Using MDA-MB-231 basal breast cancer cells expressing the GCaMP6m Ca²⁺ indicator, we showed that NCS-1 silencing did not result in major changes in cytosolic free Ca²⁺ increases as a result of endoplasmic reticulum Ca²⁺ store mobilization. However, NCS-1 silencing suppressed unstimulated basal Ca²⁺ influx. NCS-1 silencing in MDA-MB-231 cells also promoted necrotic cell death induced by the chemotherapeutic drug doxorubicin (1 µm). The effect of NCS-1 silencing on cell death was phenocopied by silencing of ORAI1, a Ca²⁺ store-operated Ca²⁺ channel that maintains Ca²⁺ levels in the endoplasmic reticulum Ca²⁺ store and whose expression was significantly positively correlated with NCS-1 in clinical breast cancer samples. This newly identified association between NCS-1 and basal breast cancers, together with the identification of the role of NCS-1 in the regulation of the effects of doxorubicin in MDA-MB-231 breast cancer cells, suggests that NCS-1 and/or pathways regulated by NCS-1 may be important in the treatment of basal breast cancers in women.

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