The current status and perspectives regarding the clinical implication of intracellular calcium in breast cancer

Calcium ions (Ca2+) act as second messengers in intracellular signaling. Ca2+ pumps, channels, sensors, and calcium binding proteins, regulate the concentrations of intracellular Ca2+ as a key regulator of important cellular processes such as gene expression, proliferation, differentiation, DNA repair, apoptosis, metastasis, and hormone secretion. Intracellular Ca2+ also influences the functions of several organelles, that include: the endoplasmic reticulum, mitochondria, the Golgi, and cell membrane both in normal and breast cancer cells. In breast cancer, the disruption of intracellular: Ca2+ homeostasis may cause tumor progression by affecting key factors/pathways including phospholipase C (PLC), inositol 1,4,5‐trisphosphate (IP3), calmodulin (CaM), nuclear factor of activated T‐cells (NFAT), calpain, calmodulin‐dependent protein kinase II (CaMKII), mitogen‐activated protein kinase (MAPK), epithelial‐mesenchymal transition (EMT), vascular endothelial growth factor (VEGF), poly (ADP‐Ribose) polymerase‐1 (PARP1), estrogen, and estrogen receptor. Because the foregoing molecules play crucial roles in breast cancer, the factors/pathways influencing intracellular Ca2+ concentrations are putative targets for cancer treatment, using drugs such as Mephebrindole, Tilapia piscidin 4, Nifetepimine, Paricalcitol, and Prednisolone. We have explored the factors/pathways which are related to breast cancer and Ca2+ homeostasis and signaling in this review, and also discussed their potential as biomarkers for breast cancer staging, prognosis, and therapy.