Expression and associated epigenetic mechanisms of the Ca2+-signaling genes in breast cancer subtypes and epithelial-to-mesenchymal transition.

Breast cancer-associated deaths are related mainly to specific molecular subtypes and the presence of metastasis. The Epithelial-to-Mesenchymal Transition (EMT) and Ca2+ signaling pathways are involved in breast cancer metastasis, and they are regulated in part by epigenetic mechanisms. Moreover, activation of EMT modulates Ca2+ concentration and in turn, Ca2+ signaling regulates the expression of EMT markers. Also, activation of Ca2+ signaling genes with epigenetic inhibitors reverts the EMT. Thus, Ca2+ signaling might have an important role in breast cancer metastasis and EMT, particularly through the epigenetic regulation of genes involved in its signaling. However, little is known due to that an estimate of 1670 genes participate in the Ca2+ signaling and only a few genes have been studied. Here, we aimed to explore the expression of all genes involved in Ca2+ signaling in all breast cancer subtypes and EMT, and whether modulation of epigenetic mechanisms is related to their expression. Several genes of the Ca2+ signaling are altered in all breast cancer subtypes, being the cadherins and voltage channels the most frequent altered genes. Also, DNA methylation and histone posttranslational modifications showed a good correlation with their altered expression. The expression of the cadherins and voltage channels is also modulated during breast EMT, and ATAC-seq results suggest that chromatin rearrangement at their promoter is involved. In conclusion, the expression of the genes involved in Ca2+ signaling is altered in all breast cancer subtypes and during EMT, and epigenetic mechanisms are an attractive target to regulate their expression.