Ca(2+) Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer

SIMPLE SUMMARY: Intracellular Ca(2+) signaling is a critical factor in breast cancer metastasis. In the proliferation stage, increases in intracellular Ca(2+) concentration through voltage-dependent Ca(2+) channels, P(2)Y(2) channels, transient receptor potential (TRP) channels, store-operated Ca(2+) channels (SOCCs), and IP(3) receptors and a decrease in intracellular Ca(2+) concentration through plasma membrane Ca(2+) ATPases and secretory pathway Ca(2+) ATPases (SPCA) activate breast cancer cell proliferation. TRPM7, SOCC, inositol trisphosphate receptor (IP(3)R), ryanodine receptor (RyR), and sarco-/endo-plasmic reticulum Ca(2+)-ATPase (SERCA) increase the expression of epithelial-to-mesenchymal transition (EMT)-related proteins; meanwhile, SPCA and the Na(+)/Ca(2+) exchanger (NCX) control the activation of EMT-related proteins. Increased Ca(2+) through TRPC1, TRPM7/8, P(2)X(7), and SOCC enhances breast cancer cell migration. The stromal interaction molecule (STIM)-Orai complex, P(2)X(7), and Ca(2+) sensing receptors are involved in invadopodia. Various pharmacological agents for Ca(2+) channels have been proposed against breast cancer and have provided potential strategies for treating metastatic processes. ABSTRACT: Metastatic features of breast cancer in the brain are considered a common pathology in female patients with late-stage breast cancer. Ca(2+) signaling and the overexpression pattern of Ca(2+) channels have been regarded as oncogenic markers of breast cancer. In other words, breast tumor development can be mediated by inhibiting Ca(2+) channels. Although the therapeutic potential of inhibiting Ca(2+) channels against breast cancer has been demonstrated, the relationship between breast cancer metastasis and Ca(2+) channels is not yet understood. Thus, we focused on the metastatic features of breast cancer and summarized the basic mechanisms of Ca(2+)-related proteins and channels during the stages of metastatic breast cancer by evaluating Ca(2+) signaling. In particular, we highlighted the metastasis of breast tumors to the brain. Thus, modulating Ca(2+) channels with Ca(2+) channel inhibitors and combined applications will advance treatment strategies for breast cancer metastasis to the brain.