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

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 expression was associated with tumor cell survival [102].

An extensive clinical study including 431 patients with invasive ductal breast carcinoma and 46 patients with fibroadenoma analyzed the expression of anoctamin 1 (Ano1, TMEM16A), one of the members in the Ano family [103]. The study identified a correlation between Ano1 overexpression and the good prognosis in patients with lower clinical stage (stage I or II) of the breast cancer or in patients with triple-negative breast cancers [103].

**3. Calcium signaling pathways as pharmacological targets in breast** 

cium concentration in both oscillating and nonoscillating MDA-MB-231 cells [78].

charged liposomes and to target only highly metastatic breast cancer cells.

**3.2. Voltage-gated calcium channels as pharmacological targets in breast cancer**

reduced by 90% the triple-negative MDA-MB-231 and MCF7 breast cancer cells [76].

Tetrodotoxin (TTX), a blocker of voltage-gated sodium channels (VGSCs), was demonstrated to diminish the number of oscillating MDA-MB-231 breast cancer cells and to reduce the amplitude and the frequency of the Ca2+ oscillations (i.e., spontaneous calcium transients) in the same cells [78]. While TTX had no effect on the basal calcium level in nonoscillating MDA-MB-231

Previous studies have demonstrated that the blockade of VGSCs inhibits the invasion of endocrine-resistant breast cancer cells [119]. It is very interesting the correlation between the blockade of VGSCs and the reduction of spontaneous calcium oscillations. Therefore, considering that only metastatic cells are characterized by spontaneous calcium transients in comparison with low-metastatic or normal cells, a possible therapeutic strategy would be to diminish calcium transients by applying targeted pharmacological agents against VGSCs. An interesting approach would be to encapsulate voltage-gated sodium channels antagonists in

1 mM Mn2+ and 0.1 mM Ni2+ ions blocked the fast activation and inactivation of the T-type

Low doses (10–20 μM) of verapamil, an antagonist of voltage-gated calcium channels, blocked the growth of triple-negative MDA-MB-231 breast cancer cells, while high doses (100 μM)

Cav3.2 channels were demonstrated to play an important role in the mechanisms involved in chemoresistance. To date, trastuzumab resistance was demonstrated to be correlated with high mRNA Cav3.2 levels in SKBR3 breast cancer cells [120]. Patients with estrogen receptor-positive breast cancer that had a poor clinical outcome presented a significant Cav3.2 upregulation [120]. Moreover, patients with HER2-positive breast cancer presented a positive correlation between the Cav3.2 expression and patient survival upon chemotherapy [120].

TRP channels have been demonstrated to be actively involved in the development and progression of breast cancer. Therefore, finding efficient strategies for blocking-/silencingspecific TRPs in breast cancer cells might represent a good strategy to diminish the breast

conditions augmented the intracellular cal-

Alterations in Calcium Signaling Pathways in Breast Cancer

http://dx.doi.org/10.5772/intechopen.80811

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**3.1. Calcium oscillations as pharmacological targets in breast cancer**

breast cells, when applied in high extracellular K<sup>+</sup>

calcium currents in MCF7 breast cancer cells [79].

**3.3. TRP channels as pharmacological targets in breast cancer**

cancer progression.

**cancer**

Integrating these results, it is still premature to evaluate if Ano1 is or is not a predictive factor in good/poor prognosis in breast cancer patients, and if it is a suitable pharmacological target. It would be very useful to have more insights into the cellular mechanisms related to Ano1 activation. In our opinion, a possible scenario would be that the opening of calcium-activated chloride channels induces chloride efflux, membrane depolarization followed by the calcium influx through VGCCs. The high level of expression of calcium-activated chloride channels in breast cancer cells might be correlated with the tendency of these cells to be more depolarized with respect to the normal surrounding cells. However, this scenario would explain only the clinical data showing the association between Ano1 overexpression and the poor prognosis in patients with breast cancer.
