TMCO1 is upregulated in breast cancer and regulates the response to pro-apoptotic agents in breast cancer cells.

The release of Ca ions from endoplasmic reticulum calcium stores is a key event in a variety of cellular processes, including gene transcription, migration and proliferation. This release of Ca often occurs through inositol 1,4,5-triphosphate receptors and the activity of these channels and the levels of stored Ca in the endoplasmic reticulum are important regulators of cell death in cancer cells. A recently identified Ca channel of the endoplasmic reticulum is transmembrane and coiled-coil domains 1 (TMCO1).

Cellular geometry and epithelial-mesenchymal plasticity intersect with PIEZO1 in breast cancer cells.

Differences in shape can be a distinguishing feature between different cell types, but the shape of a cell can also be dynamic. Changes in cell shape are critical when cancer cells escape from the primary tumor and undergo major morphological changes that allow them to squeeze between endothelial cells, enter the vasculature, and metastasize to other areas of the body. A shift from rounded to spindly cellular geometry is a consequence of epithelial-mesenchymal plasticity, which is also associated with changes in gene expression, increased invasiveness, and therapeutic resistance.

The intersection between cysteine proteases, Ca signalling and cancer cell apoptosis.

Apoptosis is a highly complex and regulated cell death pathway that safeguards the physiological balance between life and death. Over the past decade, the role of Ca signalling in apoptosis and the mechanisms involved have become clearer. The initiation and execution of apoptosis is coordinated by three distinct groups of cysteines proteases: the caspase, calpain and cathepsin families.

Intersection between calcium signalling and epithelial-mesenchymal plasticity in the context of cancer.

Epithelial-mesenchymal transition (EMT) is a form of cellular phenotypic plasticity and is considered a crucial step in the progression of many cancers. The calcium ion (Ca) acts as a ubiquitous second messenger and is implicated in many cellular processes, including cell death, migration, invasion and more recently EMT. Throughout this review, the complex interplay between Ca signalling and EMT will be explored.

AKT Regulation of ORAI1-Mediated Calcium Influx in Breast Cancer Cells.

Although breast cancer cells often exhibit both abnormal AKT signaling and calcium signaling, the association between these two pathways is unclear. Using a combination of pharmacological tools, siRNA and CRISPR/Cas9 gene silencing techniques, we investigated the association between PTEN, AKT phosphorylation and calcium signaling in a basal breast cancer cell line. We found that siRNA-mediated PTEN silencing promotes AKT phosphorylation and calcium influx in MDA-MB-231 cells.

ORAI1-Regulated Gene Expression in Breast Cancer Cells: Roles for STIM1 Binding, Calcium Influx and Transcription Factor Translocation.

A remodeling of calcium homeostasis, including calcium influx via store-operated calcium entry (SOCE), is a feature of breast cancers. SOCE is critical to maintain calcium balance in the endoplasmic reticulum calcium store and is an important mechanism for calcium signaling in a variety of cell types, including breast cancer cells. The canonical mechanism of SOCE is stromal interacting molecule 1 (STIM1)-mediated activation of ORAI.

Increased matrix stiffness suppresses ATP-induced sustained Ca influx in MDA-MB-231 breast cancer cells.

Both matrix stiffening and remodeling of calcium signaling occur in breast cancers, with downstream consequences linked to the progression of the disease. However, the potential intersection between calcium signaling and matrix stiffness has not been fully assessed in models of cancer. Here, we describe the assessment of calcium signaling in breast cancer cells at high and low matrix stiffness using novel gel culture models (gelatin methacryloyl and polydimethylsiloxane) and MDA-MB-231 breast cancer cells expressing the calcium sensor GCaMP6m.

ORAI1 regulates sustained cytosolic free calcium fluctuations during breast cancer cell apoptosis and apoptotic resistance via a STIM1 independent pathway.

Excessive rapid increases in cytosolic free Ca have a clear association with the induction of cancer cell death. Whereas, characterizing the Ca signaling events that occur during the progression of the apoptotic cascade over a period of hours or days, has not yet been possible. Now using genetically encoded Ca indicators complemented with automated epifluorescence microscopy we have shown that staurosporine-induced apoptosis in MDA-MB-231 breast cancer cells was associated with delayed development of cytosolic free Ca fluctuations, which were then maintained for 24 h.

An Emerging Role for Calcium Signaling in Cancer-Associated Fibroblasts.

Tumors exist in a complex milieu where interaction with their associated microenvironment significantly contributes to disease progression. Cancer-associated fibroblasts (CAFs) are the primary component of the tumor microenvironment and participate in complex bidirectional communication with tumor cells. CAFs support the development of various hallmarks of cancer through diverse processes, including direct cell-cell contact, paracrine signaling, and remodeling and deposition of the extracellular matrix.

Altered Calcium Influx Pathways in Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) represent an important component of the tumour microenvironment and are implicated in disease progression. Two outstanding questions in cancer biology are how CAFs arise and how they might be targeted therapeutically. The calcium signal also has an important role in tumorigenesis.

Activation of the Ion Channel TRPV4 Induces Epithelial to Mesenchymal Transition in Breast Cancer Cells.

Epithelial to mesenchymal transition (EMT) in cancer is important in therapeutic resistance and invasiveness. Calcium signaling is key to the induction of EMT in breast cancer cells. Although inhibition of specific calcium-permeable ion channels regulates the induction of a sub-set of EMT markers in breast cancer cells, it is still unclear if activation of a specific calcium channel can be a driver for the induction of EMT events.

Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels.

The ubiquitous Ca release-activated Ca (CRAC) channel is crucial to many physiological functions. Both gain and loss of CRAC function is linked to disease. While ORAI1 is a crucial subunit of CRAC channels, recent evidence suggests that ORAI2 and ORAI3 heteromerize with ORAI1 to form native CRAC channels.

Ca mediates extracellular vesicle biogenesis through alternate pathways in malignancy.

Extracellular vesicles (EVs) are small extracellular membrane vesicles that serve as important intercellular signalling intermediaries in both malignant and non-malignant cells. For EVs formed by the plasma membrane, their biogenesis is characterized by an increase in intracellular calcium followed by successive membrane and cytoskeletal changes. EV production is significantly higher in malignant cells relative to non-malignant cells and previous work suggests this is dependent on increased calcium mobilization and activity of calpain.

A new selective pharmacological enhancer of the Orai1 Ca channel reveals roles for Orai1 in smooth and skeletal muscle functions.

Store operated calcium (Ca) entry is an important homeostatic mechanism in cells, whereby the release of Ca from intracellular endoplasmic reticulum stores triggers the activation of a Ca influx pathway. Mediated by Orai1, this Ca influx has specific and essential roles in biological processes as diverse as lactation to immunity. Although pharmacological inhibitors of this Ca influx mechanism have helped to define the role of store operated Ca entry in many cellular events, the lack of isoform specific modulators and activators of Orai1 has limited our full understanding of these processes.

Transient receptor potential cation channel subfamily V and breast cancer.

Transient receptor potential cation channel subfamily V (TRPV) channels play important roles in a variety of cellular processes. One example includes the sensory role of TRPV1 that is sensitive to elevated temperatures and acidic environments and is activated by the hot pepper component capsaicin. Another example is the importance of the highly Ca selective channels TRPV5 and TRPV6 in Ca absorption/reabsorption in the intestine and kidney.

Assessment of doxorubicin-induced remodeling of Ca signaling and associated Ca regulating proteins in MDA-MB-231 breast cancer cells.

Triple-negative breast cancers (TNBC) are often associated with high relapse rates, despite treatment with chemotherapy agents such as doxorubicin. A better understanding of the signaling and molecular changes associated with doxorubicin may provide novel insights into strategies to enhance treatment efficacy. Calcium signaling is involved in many pathways influencing the efficacy of chemotherapy agents such as proliferation and cell death.

NCS-1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin.

Neuronal calcium sensor-1 (NCS-1) is a positive modulator of IP receptors and was recently associated with poorer survival in breast cancers. However, the association between NCS-1 and breast cancer molecular subtypes and the effects of NCS-1 silencing on calcium (Ca ) signaling in breast cancer cells remain unexplored. Herein, we report for the first time an increased expression of NCS-1 in breast cancers of the basal molecular subtype, a subtype associated with poor prognosis.

Differential engagement of ORAI1 and TRPC1 in the induction of vimentin expression by different stimuli.

The Ca signal is essential in both hypoxia- and epidermal growth factor (EGF)-mediated epithelial to mesenchymal transition (EMT) in MDA-MB-468 breast cancer cells. This finding suggests that Ca-permeable ion channels participate in the induction of expression of some mesenchymal markers such as vimentin. However, the ion channels involved in vimentin expression induction have not been fully characterized.

The Calcium-Signaling Toolkit in Cancer: Remodeling and Targeting.

Processes that are important in cancer progression, such as sustained cell growth, invasion to other organs, and resistance to cell death inducers, have a clear overlap with pathways regulated by Ca signaling. It is therefore not surprising that proteins important in Ca signaling, sometimes referred to as the "Ca signaling toolkit," can contribute to cancer cell proliferation and invasiveness, and the ability of agents to induce cancer cell death. Ca signaling is also critical in other aspects of cancer progression, including events in the tumor microenvironment and processes involved in the acquisition of resistance to anticancer therapies.

ORAI1 and ORAI3 in Breast Cancer Molecular Subtypes and the Identification of ORAI3 as a Hypoxia Sensitive Gene and a Regulator of Hypoxia Responses.

The remodeling of specific calcium-permeable ion channels is a feature of some breast cancer subtypes. ORAI1 is a protein that forms a calcium-permeable ion channel responsible for store-operated calcium entry (SOCE) in a variety of cell types. ORAI3, a related isoform, is not a regulator of SOCE in most cell types.

Calcium signalling and breast cancer.

The past two decades have seen the identification of important roles for calcium signalling in many of the hallmarks of cancer. One of the cancer types that has been a particular focus of such studies is breast cancer. The breast is intrinsically linked to the calcium ion due to the importance of milk calcium in neonatal growth and development.

Pharmacological inhibition of store-operated calcium entry in MDA-MB-468 basal A breast cancer cells: consequences on calcium signalling, cell migration and proliferation.

Store-operated Ca entry is a pathway that is remodelled in a variety of cancers, and altered expression of the components of store-operated Ca entry is a feature of breast cancer cells of the basal molecular subtype. Studies of store-operated Ca entry in breast cancer cells have used non-specific pharmacological inhibitors, complete depletion of intracellular Ca stores and have mostly focused on MDA-MB-231 cells (a basal B breast cancer cell line). These studies compared the effects of the selective store-operated Ca entry inhibitors Synta66 and YM58483 (also known as BTP2) on global cytosolic free Ca ([Ca]) changes induced by physiological stimuli in a different breast cancer basal cell line model, MDA-MB-468.

ORAI channels and cancer.

Cancer is a major cause of death. The diversity of cancer types and the propensity of cancers to acquire resistance to therapies, including new molecularly targeted and immune-based therapies, drives the search for new ways to understand cancer progression. The remodelling of calcium (Ca) signalling and the role of the Ca signal in controlling key events in cancer cells such as proliferation, invasion and the acquisition of resistance to cell death pathways is well established.