Cancer-Associated Intermediate Conductance Ca2+-Activated K+ Channel KCa3.1

Figure 1. KCNN4 mRNA expression levels in breast cancer and their association with patient survival. (A) mRNA expression levels of KCNN1-4 coding for SK1-SK3 and KCa3.1 were compared between healthy and breast tumor tissues, measured by RNA sequencing as fragments per kilobase of transcript per million mapped reads (FPKM). Data obtained from The Cancer Genome Atlas [30] revealed no significant difference in a Kruskal–Wallis test with Dunn’s test for multiple comparisons (α = 0.05 for n = 113 healthy and n = 1095 breast tumor tissues). (B) In the Kaplan–Meier plotter [31], significantly prolonged overall survival (OS) was associated with low KCNN4 mRNA levels. Groups were statistically compared by log-rank test (hazard ratio = 1.37 (confidence interval 1.08–1.72) for n = 1030 low and n = 372 high KCNN4-expressing tumors).

Figure 2. Tumorigenesis, progression, and CD45 status in MMTV-PyMT WT and KCa3.1 KO mice. Tumor-free survival (TFS) and overall survival (OS) were studied in spontaneous breast cancer-prone MMTV-PyMT wildtype (WT) and KCa3.1 KO mice. At a diameter of 15 mm, tumors were harvested for investigating immune cell infiltration. (A) As previously reported [71], tumorigenesis and tumor progression measured by TFS and OS, respectively, were not dependent on MMTV-PyMT WT or KCa3.1 KO genotypes (n = 6 each). (B) Staining against the CD45 pan leukocyte marker revealed moderate immune cell infiltration in WT tumors (green), which was absent in KCa3.1 KO. Immune cells were generally more abundant in the tumor-surrounding stroma of WT mice, but mostly absent in KCa3.1 KO tumor samples. DAPI labelling was performed to visualize nuclei. Results are presented as means ± SEM for n = 4 stroma sections and n = 5 tumor sections of MMTV-PyMT WT (black squares) or KCa3.1 KO (red squares) genotypes. Unpaired t-tests differentiated between groups with ** p < 0.01 and *** p < 0.001.

Figure 3. Role of the KCa3.1 channel in tumor-associated cells. Tumors from different entities and various microenvironmental cell types, i.e., immune cells, vasculature, fibroblasts (not shown) express functional KCa3.1 channels. Physiological roles and tumor behaviors of KCa3.1 are cell type-dependent, but involve proliferation, migration and cancer progression. KCa3.1 channel expression seems to be a crucial determinant of cancer risk and, in established cancers, KCa3.1 upregulation at the end of G1 phase of the cell cycle was seen in various tumor cell types [36]. By its interaction with [Ca2+]i via its constitutively bound calmodulin (CaM), with other ion channels such as TRP or STIM/Orai, with changes in the membrane potential (Vm), and with apoptotic pathways, KCa3.1 may further contribute to aberrant tumor cell signaling. Beyond that, tumor-promoting KCa3.1 activity in stromal cells has been described. Several studies find evidence for KCa3.1 expression in endothelial and in activated smooth muscle cells of the vasculature pointing to its role in tumor angiogenesis and/or vasculogenesis. Moreover, growth factor signaling was linked to KCa3.1 in fibroblasts to promote…