**2.2. Voltage-gated calcium channels in breast cancer**

initiator that bluntly recruits calcium-dependent apoptotic effectors such as calpain and caspase 12, in both breast cancer cells and adipocytes. Some studies suggested that inducing apoptosis with vitamin D3, particularly in the tumor-surrounding adipose tissue involved in tumor progression, can contribute to the antitumoral effects of this hormone and may be of real therapeutic interest to include calcium-dependent apoptotic proteases as molecular targets for new therapeutic and preventive agents in breast cancer and obese patients [56].

Recently, several papers were describing the presence of a new cellular type—the telocytes (TCs)—in the stroma of the mammary gland [57–59]. TCs are characterized by a small cellular body and extremely long telopodes with alternative regions of dilations called podoms and veillike cytoplasmic extensions called podomeres [60–62]. Although there are numerous attempts to differentiate these cells from other cellular types such as fibroblasts, endothelial cells, mesenchymal stem cells, immune cells, a specific immunohistochemical marker was still not found [63]. The most specific markers, which are nowadays used for their identification, are CD34 and PDGFR alpha or beta [64, 65]. Genomic and proteomic approaches were also used to determine their uniqueness and have shown that telocytes are distinct from the other types listed above [66–70]. Mou et al. investigated the immunohistochemical characteristics and potential functions of TCs in reconstituted breast cancer tissue and found that they express c-kit/CD117, CD34, and vimentin. A very interesting observation is that TCs communicate with breast cancer cells as well as with other stromal cells [58, 71, 72]. Together with other stromal cells, TCs inhibited the breast cancer cell apoptosis and facilitated their proliferation and the formation of typical

Rusu et al. described in an immunohistochemical study some CD34+/CD10±/c-kit-/vimentincells found in the inter- and intralobular stroma, which they considered to be TCs and suggested a stem cell-like features based on the expressed markers and changing phenotype [59]. Although a lot of studies are needed to talk about a certain function of TCs, a possible contribution to the mechanisms of carcinogenesis is not negligible, by the modification of the tumor microenvironment. As our team previously showed, TCs are not pacemakers but modulate the activity of the surrounding cells using calcium signaling [73]. Our results showed that uterine TCs express T-type calcium channels that might play a role in the generation of endogenous bioelectric signals responsible for the regulation of the surrounding cell behavior [74, 75].

The most important proteins coupled with calcium signaling pathways and that have been

The resting potential of human breast adenocarcinoma cells (estrogen receptor-positive MCF7 and triple-negative MDA-MB-231) is more positive (with approximately 27–30 mV) than normal

*1.1.5. Human breast telocytes*

172 Calcium and Signal Transduction

nest structure assembly in breast cancer, in vitro [58].

**2. Calcium signaling alterations in breast cancer**

**2.1. Resting potential and calcium oscillations in breast cancer**

described as key players in breast cancer cells are summarized in **Figure 2**.

Patch-clamp studies on human mammary epithelial cells (HMEC) indicated the absence of voltage-gated calcium currents [79].

The contribution of T-type calcium channels to breast cancer was investigated in several studies. To date, the expression of the α1H subunit, but not the α1C or α1G subunits, of the voltage-gated calcium channels was demonstrated in MCF-7 breast cancer cells [80]. Among T-type calcium channels, Cav3.1, but not Cav3.2, was demonstrated to play an important role in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells [81]. Patch-clamp recordings demonstrated the presence of T-type voltage-gated calcium currents (ICaT) in MCF7 breast cancer cells [79].

The expression of Orai3 was identified to be higher in MCF-7 breast cancer cells versus normal MCF-10A mammary epithelial cells, while its silencing inhibits the MCF-7 cell proliferation, arrests the cell cycle in the G1 phase, downregulates cyclin-dependent kinases 4/2, cyclins E and D1, and determines the accumulation of p21(Waf1/Cip1) (a cyclin-dependent kinase

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In STIM1 siRNA- or Orai1 siRNA-treated MDA-MB-231 human breast tumor cells, a reduction in the migration process was identified [95]. Additionally, overexpression of STIM1 and Orai1 in MCF-10A epithelial cells increased their invasiveness [95]. Experiments on immunodeficient NOD/SCID mice injected with MDA-MB-231 human breast tumor cells were stably transfected with STIM1 siRNA, or Orai1 siRNA, but not with control siRNA, which demon-

Interestingly, a signaling pathway independent of endoplasmic reticulum calcium stores or STIM1 and STIM2 protein activation was identified in MCF-7 breast cancer cells (the secretory pathway calcium ATPase 2 (SPCA2)/Orai1 signaling) [96], where SPCA2 is located in the

breast cancer cells invasiveness. To date, blocking or silencing hEag1 channels in MDA-MB-231 breast cancer cells induces membrane depolarization and subsequent diminishment of Ca2+

MCF-7 breast cancer cells, involved in the cell proliferation in a dose-dependent manner and

eral breast cancer cell lines (e.g., UACC893, SK-BR-3, and MDA-MB-231) [99]. Intermediate-

breast cancer cells, and their current density and basal cytosolic Ca2+ concentration being augmented in cells synchronized at the end of the G1 or S phase with respect to the cells in the early G1 phase [100]. Caveolin-1 was demonstrated to colocalize with BKCa in MCF-7 breast cancer cells, and silencing caveolin-1 induces increased activation and upregulation

Calcium-activated chloride channel anoctamin 1 (ANO1) was demonstrated to be highly expressed in breast cancer cell lines and primary tumors and was considered to be a predictive factor for the disease degree and poor prognosis [102]. ANO1 activation was demonstrated to be done via the EGF receptor and calmodulin-dependent protein kinase II signaling, and its

channels (BKCa) were described to be expressed in sev-

channels (hIK1) are also functionally expressed in MCF7

channels in

channels (hIKCa1) in

 **channels in breast cancer**

Several pieces of evidence indicate the role played by Ether à go-go (hEag1) K<sup>+</sup>

influx through Orai1, which affects cell migration and proliferation [97].

Prolactin increases the current density of the human Ca2+-activated K<sup>+</sup>

activating the Janus kinase (JAK2)-coupled cytokine receptor pathway [98].

**2.6. Calcium-activated potassium channels in breast cancer**

**2.7. Calcium-activated chloride channels in breast cancer**

expression was associated with tumor cell survival [102].

inhibitor) and p53 (a tumor-suppressing protein) [94].

strated the inhibition of metastasis [95].

Golgi apparatus.

**2.5. Ether à go-go (hEag1) K+**

Large conductance Ca2+-activated K<sup>+</sup>

conductance, Ca2+-activated K<sup>+</sup>

of BKCa [101].

A meta-analysis of public microarray datasets in clinical cancer tissue samples identified the upregulation of several VGCCs transcripts (e.g., *CACNA1C*, *CACNA1D*, *CACNA1B*, *CACNA1G*, and *CACNA1I*) in breast cancer and their involvement in the development and cancer progression [82]. Oppositely, another meta-analysis indicated the downregulation of the same VGCCs transcripts in breast cancer [83].
