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.

中文翻译：

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NCS-1在基础乳腺癌中的表达较高，并调节钙流入和对阿霉素的细胞毒性反应。

神经钙传感器1（NCS-1）是IP3受体的正调节剂，最近与乳腺癌患者的生存期较差有关。然而，NCS-1和乳腺癌分子亚型之间的联系以及NCS-1沉默对乳腺癌细胞中钙（Ca2 +）信号传导的影响尚待探索。在本文中，我们首次报道了基础分子亚型（与不良预后相关的亚型）的乳腺癌中NCS-1表达的增加。使用表达GCaMP6m Ca2 +指示剂的MDA-MB-231基础乳腺癌细胞，我们显示NCS-1沉默并未导致内质网Ca2 +存储动员导致胞质游离Ca2 +增加的主要变化。但是，NCS-1沉默抑制了未刺激的基础Ca2 +内流。MCS-MB-231细胞中的NCS-1沉默还促进了化疗药物阿霉素（1 µm）诱导的坏死细胞死亡。NAI-1沉默对细胞死亡的影响通过ORAI1沉默表现出来，ORAI1是一种由Ca2 +存储操作的Ca2 +通道，可维持内质网Ca2 +存储中的Ca2 +水平，并且其表达与临床乳腺癌样本中的NCS-1呈显着正相关。NCS-1与基础乳腺癌之间的这种新发现的关联，以及NCS-1在调节阿霉素对MDA-MB-231乳腺癌细胞作用中的作用的鉴定，表明NCS-1和/或NCS-1调控的信号通路在女性基础性乳腺癌的治疗中可能很重要。NAI-1沉默对细胞死亡的影响通过ORAI1沉默表现出来，ORAI1是一种由Ca2 +存储操作的Ca2 +通道，可维持内质网Ca2 +存储中的Ca2 +水平，并且其表达与临床乳腺癌样本中的NCS-1呈显着正相关。NCS-1与基础乳腺癌之间的这种新发现的关联，以及NCS-1在调节阿霉素对MDA-MB-231乳腺癌细胞作用中的作用的鉴定，表明NCS-1和/或NCS-1调控的信号通路在女性基础性乳腺癌的治疗中可能很重要。NAI-1沉默对细胞死亡的影响通过ORAI1沉默表现出来，ORAI1是一种由Ca2 +存储操作的Ca2 +通道，可维持内质网Ca2 +存储中的Ca2 +水平，并且其表达与临床乳腺癌样本中的NCS-1呈显着正相关。NCS-1与基础乳腺癌之间的这种新发现的关联，以及NCS-1在调节阿霉素对MDA-MB-231乳腺癌细胞作用中的作用的鉴定，表明NCS-1和/或NCS-1调控的信号通路在女性基础性乳腺癌的治疗中可能很重要。由Ca2 +存储操作的Ca2 +通道，可维持内质网Ca2 +存储中的Ca2 +水平，并且其表达与临床乳腺癌样本中的NCS-1显着正相关。NCS-1与基础乳腺癌之间的这种新发现的关联，以及NCS-1在调节阿霉素对MDA-MB-231乳腺癌细胞作用中的作用的鉴定，表明NCS-1和/或NCS-1调控的信号通路在女性基础性乳腺癌的治疗中可能很重要。由Ca2 +存储操作的Ca2 +通道，可维持内质网Ca2 +存储中的Ca2 +水平，并且其表达与临床乳腺癌样本中的NCS-1显着正相关。NCS-1与基础乳腺癌之间的这种新发现的关联，以及NCS-1在调节阿霉素对MDA-MB-231乳腺癌细胞作用中的作用的鉴定，表明NCS-1和/或NCS-1调控的信号通路在女性基础性乳腺癌的治疗中可能很重要。