NCS-1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin
Bong, AHL; Robitaille, M; Milevskiy, MJG; Roberts-Thomson, SJ; Monteith, GR
Journal Article in press
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 signaling in breast cancer cells remains 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 Ca(2+) indicator, we showed that NCS-1 silencing did not result in major changes in cytosolic free Ca(2+) increases as a result of ER Ca(2+) store mobilization. However, NCS-1 silencing suppressed unstimulated basal Ca(2+) influx. NCS-1 silencing in MDA-MB-231 cells also promoted necrotic cell death induced by the chemotherapeutic drug doxorubicin (1 microM). The effect of NCS-1 silencing on cell death was phenocopied by silencing of ORAI1, a Ca(2+) store-operated Ca(2+) channel that maintains Ca(2+) levels in the endoplasmic reticulum Ca(2+) 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, suggest that NCS-1 and/or pathways regulated by NCS-1 may be important in the treatment of basal breast cancers in women.