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.