Calcium influx pathways in breast cancer: opportunities for pharmacological intervention

Abstract

Ca2+ influx through Ca 2+ permeable ion channels is a key trigger and regulator of a diverse set of cellular events, such as neurotransmitter release and muscle contraction. Ca 2+ influx is also a regulator of processes relevant to cancer, including cellular proliferation and migration. This review focuses on calcium influx in breast cancer cells as well as the potential for pharmacological modulators of specific Ca 2+ influx channels to represent future agents for breast cancer therapy. Altered expression of specific calcium permeable ion channels is present in some breast cancers. In some cases, such changes can be related to breast cancer subtype and even prognosis. In vitro and in vivo models have now helped identify specific Ca 2+ channels that play important roles in the proliferation and invasiveness of breast cancer cells. However, some aspects of our understanding of Ca 2+ influx in breast cancer still require further study. These include identifying the mechanisms responsible for altered expression and the most effective therapeutic strategy to target breast cancer cells through specific Ca 2+ channels. The role of Ca 2+ influx in processes beyond breast cancer cell proliferation and migration should become the focus of studies in the next decade. [Ca 2+ ]CYT, cytoplasmic-free calcium; A-804598, N-cyano-N″-[(1S)-1-phenylethyl]-N'-5-quinolinyl-guanidine; EC, endothelial cells; EMT, epithelial to mesenchymal transition; ER + , oestrogen positive; ERα, oestrogen receptor α; ErbB2 (also known as HER2), human EGF receptor 2; IP3, inositol Abbreviations

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

“…In addition, by modifying the membrane potential, K + channels regulate voltage‐dependent activity and/or conductivity of Ca 2+ entry pathways (Huang and Jan, 2014; Huber, 2013). Because Ca 2+ is an ubiquitous intracellular messenger relevant for cell survival, apoptosis and proliferation (Azimi et al ., 2014; Monteith et al ., 2007), it was proposed that breast tumour K Ca channels promote pro‐oncogenic functions at least in part by Ca 2+ ‐dependent signalling pathways (Kunzelmann, 2005; Ouadid‐Ahidouch and Ahidouch, 2013). Oscillations of [Ca 2+ ] i have been observed during exit from G 1 , during S phase, and at the end of M phase (Parkash and Asotra, 2010; Santella et al ., 2005).…”

Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

“…These classes have clear differences in their mechanism of activation. For example the Orai1 protein is part of a complex whereby Ca 2+ influx is activated by the depletion of endoplasmic reticulum Ca 2+ stores (Azimi et al 2014). In contrast, TRP channels have been described as sensors, as exemplified by TRPV1 a Ca 2+ permeable ion channel activated by heat and the hot chilli component, capsaicin (Azimi et al 2014).…”

“…For example the Orai1 protein is part of a complex whereby Ca 2+ influx is activated by the depletion of endoplasmic reticulum Ca 2+ stores (Azimi et al 2014). In contrast, TRP channels have been described as sensors, as exemplified by TRPV1 a Ca 2+ permeable ion channel activated by heat and the hot chilli component, capsaicin (Azimi et al 2014). Other ligand gated calcium channels include ionotropic glutamate receptors and also P2X channels that are activated by some nucleosides (e.g.…”

“…Other ligand gated calcium channels include ionotropic glutamate receptors and also P2X channels that are activated by some nucleosides (e.g. ATP) whereas VGCCs are activated by changes in membrane potential (Azimi et al 2014). Even within classes of Ca 2+ channels there is great diversity of activators (e.g.…”

Endocrine disrupting chemicals as the potential risk factor for estrogen-dependent cancers

“…76 It was also reported that chemoresistance in both ERα-positive and ERα-negative breast cancer cells might be linked with the exposure to low doses of BPA. 77 As slow-dividing progenitor cells are more vulnerable to the environmental factors and epigenetic mechanisms, 78 some studies confirming this theory have been conducted.…”