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T-Type Voltage Gated Calcium Channels: a Target in Breast Cancer?

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T-Type Voltage Gated Calcium Channels: a Target in Breast Cancer? Breast Cancer Research and Treatment (2019) 173:11–21 https://doi.org/10.1007/s10549-018-4970-0 REVIEW T-Type voltage gated calcium channels: a target in breast cancer? Anamika Bhargava1 · Sumit Saha1 Received: 24 July 2018 / Accepted: 15 September 2018 / Published online: 21 September 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Purpose The purpose of this review article is to discuss the potential of T-type voltage gated calcium channels (VGCCs) as drug targets in breast cancer. Summary Breast cancer, attributable to the different molecular subtypes, has a crucial need for therapeutic strategies to counter the mortality rate. VGCCs play an important role in regulating cytosolic free calcium levels which regulate cellular processes like tumorigenesis and cancer progression. In the last decade, T-type VGCCs have been investigated in breast cancer proliferation. Calcium channel blockers, in general, have shown an anti-proliferative and cytotoxic effects. T-type VGCC antagonists have shown growth inhibition owing to the inhibition of Ca V3.2 isoform. Ca V3.1 isoform has been indicated as a tumour-suppressor gene candidate and is reported to support anti-proliferative and apoptotic activity in breast cancer. The distribution of T-type VGCC isoforms in different breast cancer molecular subtypes is diverse and needs to be further investigated. The role of T-type VGCCs in breast cancer migration, metastasis and more importantly in epithelial to mesen- chymal transition (EMT) is yet to be elucidated. In addition, interlaced therapy, using a combination of chemotherapy drugs and T-type VGCC blockers, presents a promising therapeutic approach for breast cancer but more validation and clinical trials are needed. Also, for investigating the potential of T-type VGCC blocker therapy, there is a need for isoform-specific agonists/antagonists to define and discover roles of T-type VGCC specific isoforms. Conclusion Our article provides a review of the role of T-type VGCCs in breast cancer and also discusses future of the research in this area so that it can be ascertained whether there is any potential of T-type VGCCs as drug targets in breast cancer. Keywords Breast cancer · Voltage gated calcium channel · T-type VGCCs · Calcium influx Introduction channels are mostly ligand-gated ion channels that open in response to a ligand and mediate cation flux [3–5]. Two main 2+ 2 + Changes in the cytosolic free Ca concentration [Cai ] rep- classes of calcium selective channels are known, namely resent an important signalling mechanism, which integrates store-operated calcium channels and voltage gated calcium other signal-transduction cascades and controls a variety channels (VGCCs) [6, 7]. Store-operated calcium channels of cellular processes [1]. Although there are many types of like Orai mediate calcium influx in response to the deple- calcium permeable ion channels like IP3 (Inositol Triphos- tion of intracellular calcium stores. VGCCs include L-type, phate) and RYR receptor (Ryanodine Receptor) isoforms N-type, T-type, R-type and P/Q-type. These ion channels expressed in the intracellular organelles [2], plasma mem- consist of different subunits, although it is the α1 subu- brane has its own share of calcium permeable ion channels nit of 190–250 kDa that forms the calcium selective pore which we can classify into calcium selective and calcium [8]. The α1 subunit also determines the type of VGCC [9]. non-selective channels (Fig. 1). Calcium non-selective ion The genes that encode the α1 subunit include CACNA1S (CaV1.1), CACNA1C (CaV1.2), CACNA1D (CaV1.3) and CACNA1F (CaV1.4) for L-type calcium channels; CACNA1A * Anamika Bhargava (CaV2.1), CACNA1B (CaV2.2) and CACNA1E (CaV2.3) for [email protected] P-/Q-type, N-type and R-type calcium channels respectively; 1 and CACNA1G (Ca 3.1), CACNA1H (Ca 3.2) and CAC- Ion Channel Biology Lab, Department of Biotechnology, V V Indian Institute of Technology Hyderabad (IITH), Kandi, NA1I (CaV3.3) for T-type calcium channel isoforms [10]. Telangana 502285, India Vol.:(0123456789)1 3 12 Breast Cancer Research and Treatment (2019) 173:11–21 Fig. 1 Calcium influx chan- nels on the plasma membrane. Calcium selective channels comprise of Orai and CaV family. Calcium non-selective channels comprise of P2X, 5-HT3 receptor, TRP channels, NMDA, AMPA and kainate receptors. NMDA, AMPA and kainate receptors are predomi- nantly found in neurons Although VGCCs have important roles in the excitability of CaV1 (L-type) and CaV2 (P/Q, N and R-type) channels but excitable cells, such as those in the central nervous system they are only ∼ 25% identical in the amino acid sequence [9]. and cardiovascular tissue, they are also expressed in non- Currents through T-type α1 subunit are similar to currents excitable cell types where they perform a variety of cellular through native T-type VGCCs, suggesting that the β, α2δ and functions. In the last decade, they have also been implicated γ subunits may have alternative roles [17]. The alternative in cancer cells where they have been found to both promote roles of auxiliary subunits have recently been reviewed by or inhibit proliferation depending on the type of cancer and Hofmann et al. [18] which also includes essential physi- the type of ion channel isoform expressed [11]. ological processes. VGCCs have been reported as promising target can- T-type VGCCs perform various functions such as atrial didates in cancer therapy [12]. Among VGCCs, T-type pacemaking, low-threshold exocytosis, neuronal firing, G1/S VGCCs are being suggested as a promising target as they checkpoint regulation, cell proliferation, atrioventricular have been reported to be upregulated in many cancer types. regulation etc. [20–25]. T-type VGCCs are therefore impli- For detailed information on the role of T-type VGCCs in cated in several pathologies including autism, hypertension, cancer growth and progression, please see reviews [13–15]. epilepsy and cancer. Because of the extreme importance of Our review is focussed on the role of T-type VGCCs in T-type VGCCs and their abundant expression in the nervous breast cancer and future opportunities therein to validate system, a major disease that involves the T-type VGCC as a them as potential drug targets in breast cancer. In this review drug target is absence epilepsy. Experiments on the GAERS we have covered (1) The data indicating the role of T-type (Genetic Absence Epilepsy Rat of Strasbourg) mice showed VGCCs in breast cancer and (2) The scope of research in this that there was a marked increase in the activity of Ca V3.2 area to elucidate the direct/ indirect role of T-type VGCCs in isoform of T-type VGCCs which triggers the burst firing breast cancer regulation. We have reviewed the involvement of thalamic neurons in epilepsy seizure [26]. The Ca V3.2 of T-type VGCCs in breast cancer among the vast number of isoform of T-type VGCCs is also reported to be upregu- cancers due to the following reasons: (1) Breast cancer has lated in visceral and neuropathic pain [27] in animal models, a huge mortality rate, (2) Due to varied molecular subtypes, where CaV3.2 contributes to the perception of pain and is prognosis and therapy is a challenge in breast cancer and (3) regarded as a viable drug target. The evidence of involve- Reports regarding the role of T-type VGCCs in breast cancer ment of T-type VGCCs in the manifestation of diseases such are insufficient, inconclusive and non-specific to come up as cardiovascular diseases, renal injury and different human with definitive therapies. cancers such as breast, colon, prostate, leukaemia, ovarian and melanoma is supported by their over/re-expression in T‑type voltage gated calcium channels cancerous and diseased tissue as compared to the normal tissue [24, 28–34]. Various studies have also indicated their Originally, Hagiwara and colleagues described two inward supportive role in cancer proliferation, survival and cell- currents, labelled I and II, in starfish eggs which were both cycle regulation in cancer progression. However, a clear calcium influx currents [16]. Today, “I” and “II” are widely casual or consequential relationship of T-type VGCCs with recognized as high-voltage activated (HVA) and low-volt- the various above said diseases is not well established. age activated (LVA) channels respectively. T-type VGCCs belong to the family of LVA channels [17]. Three isoforms Breast carcinoma of the T-type (CaV3) VGCC α1 subunit have been discovered by cDNA cloning and sequencing (Table 1). These calcium Breast cancer is emerging as the most common female channel subunits have the same molecular organization as cancer worldwide which, according to the World Cancer 1 3 Breast Cancer Research and Treatment (2019) 173:11–21 13 Table 1 T-Type voltage gated calcium channel properties. adapted from [17, 19] T-Type VGCCs CaV3.1 CaV3.2 CaV3.3 Other names α13.1, α1G α13.2, α1H α13.3, α1I Molecular information Human: 2377aa, O43497, chr. Human: 2353aa, O95180, chr. Human: 2251aa, AAM67414, chr. 17q22, CACNA1G 16p13.3, CACNA1H 22q13.1, CACNA1I Ion selectivity Sr2+ > Ba2+ = Ca2+ Ba2+ = Ca2+ Ba2+ = Ca2+ Blockers Selective: NNC 55 0396 Selective: NNC 55 0396 Selective: NNC 55 0396 Non-selective: Nickel, Mibefradil, Non-selective: Nickel, Mibefradil, Non-selective: Nickel, Mibefradil Nimopidine and Amiloride Nimopidine and anaesthetics Note CaV3.2 is more sensitive than CaV3.1 to block by nickel (IC50 = 12 µl) Functional assays Patch-clamp, calcium imaging Patch-clamp, calcium imaging Patch-clamp, calcium imaging Channel Distribution (in general) Brain, Ovary, Placenta, Heart Kidney, Liver, Adrenal cortex, Brain Brain, Heart Physiological function Thalamic oscillations, muscle Thalamic oscillations, muscle Thalamic oscillations, muscle contraction contraction contraction T-type VGCCs can be divided into three subclasses: CaV3.1, CaV3.2 and CaV3.3 Currently, the only major means of restricting mortal- Table 2 Breast cancer subtypes with their specific endocrine receptor ity in breast cancer is early screening [43].
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