Abstract
Simple SummaryBreast cancer is the most frequently diagnosed malignant tumor and the second leading cause of cancer death in women worldwide. The risk of developing breast cancer is 12.8%, i.e., 1 in 8 people, and a woman’s risk of dying is approximately 1 in 39. Calcium signals play an important role in various cancers and transport calcium ions may have altered expression in breast cancer, such as the TRPM7 calcium permeant ion channel, where overexpression may be associated with a poor prognosis. This review focuses on the TRPM7 channel, and the oncogenic roles studied so far in breast cancer. The TRPM7 ion channel is suggested as a potential and prospective target in the diagnosis and treatment of breast cancer.The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a divalent cations permeant channel but also has intrinsic serine/threonine kinase activity. It is ubiquitously expressed in normal tissues and studies have indicated that it participates in important physiological and pharmacological processes through its channel-kinase activity, such as calcium/magnesium homeostasis, phosphorylation of proteins involved in embryogenesis or the cellular process. Accumulating evidence has shown that TRPM7 is overexpressed in human pathologies including breast cancer. Breast cancer is the second leading cause of cancer death in women with an incidence rate increase of around 0.5% per year since 2004. The overexpression of TRPM7 may be associated with a poor prognosis in breast cancer patients, so more efforts are needed to research a new therapeutic target. TRPM7 regulates the levels of Ca2+, which can alter the signaling pathways involved in survival, cell cycle progression, proliferation, growth, migration, invasion, epithelial-mesenchymal transition and thus determines cell behavior, promoting tumor development. This work provides a complete overview of the TRPM7 ion channel and its main involvements in breast cancer. Special consideration is given to the modulation of the channel as a potential target in breast cancer treatment by inhibition of proliferation, migration and invasion. Taken together, these data suggest the potential exploitation of TRPM7 channel-kinase as a therapeutic target and a diagnostic biomarker.
Highlights
Downregulation of the activities of the transient receptor potential melastatin-subfamily member 7 (TRPM7) channel could regulate a reduction in the level of c-FLIPL protein promoting the activation of caspase-8, improving apoptosis and decreasing the expression of c-FLIPS. This results in TRAIL-induced apoptosis via the formation of death-induced signaling complexes (DISC) [110]. These results highlight the role of TRPM7 in the apoptotic resistance of breast cancer cells and indicate several processes that can induce cell death depending on cell types
The TRPM7 channel has been shown to be overexpressed in breast carcinoma with associated microcalcifications and it is an important player of Ca2+ and Mg2+ influx regulation in breast cancer [130]
In breast cancer cell lines MDA-MD-231 and MDA-MD-468 (TNBC cells), NS8593 suppresses TRPM7 Mg2+ -dependent currents [140], increasing the apoptotic and antiproliferative effects induced by TRAIL via a decrease in c-FLIP as well as suppressing the phosphorylation of STAT3, respectively [109,111]
Summary
Li et al demonstrated repeatedly that in patients treated for hypertension or other cardiovascular diseases, with calcium channel blockers (CCB), this would increase the risk, by up to two times, of developing breast cancer and following a dose long term, which is supported by other studies [13,14,15]. More recent studies do not suggest any increased risk of developing breast cancer with long-term or punctual CCB intake, nor is it associated with greater mortality [16,17] and would protect against a risk of recurrence in women aged 20 to 54 [18]. The use of CCB in breast cancer patients could be associated with the development of lymphedema as well as immunosuppressive effects within the tumor microenvironment [19,20], justifying the importance of calcium in breast cancer. We will present the bulk of current knowledge on the role of the TRPM7 ion channel in the initiation and progression of breast cancer, as a potential therapeutic target
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