Calcium influx pathways in breast cancer: opportunities for pharmacological intervention

Abstract

Ca(2+) 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.

Keywords: breast cancer; calcium channels; calcium influx; calcium signalling; oncology.

Figure 1

Schematic depiction of some of the Ca²⁺ channels, pumps and exchangers involved in Ca²⁺ signalling in mammalian cells. Ca²⁺ influx channels include the ORAI1 channel (an example of a store-operated Ca²⁺ entry channel), L-type Ca²⁺ channels (an example of a voltage-gated Ca²⁺ channel), P2X receptor channel (an example of a ligand-gated Ca²⁺ channel) and TRP channels (channels that vary in their Ca²⁺ selectivity). GPCRs increase [Ca²⁺]_CYT via PLC-mediated generation of IP₃ and activation of IP₃R. [Ca²⁺]_CYT levels are sustained at low levels through the active efflux of Ca²⁺ by PMCAs and Na⁺/Ca²⁺ exchangers on the plasma membrane. Sequestration of Ca²⁺ into the ER Ca²⁺ store is mediated by SERCA, into the mitochondria by mitochondrial Ca²⁺ uniporter (MCU) and into the Golgi by secretory pathway Ca²⁺-ATPase (SPCA). Increases in [Ca²⁺]_CYT can result in the activation of calcineurin (CaN) that phosphorylates the transcription factor NFAT, which after translocation into the nucleus regulates gene transcription (Crabtree, 1999). Calcium can also activate many cytosolic proteins with Ca²⁺-sensitivity confirmation and activities such as calpain, which can regulate a number of important cellular processes including cytoskeletal remodelling and motility (Storr et al., 2011).

Figure 2

Ca²⁺ influx pathways. Examples of influx pathways and naturally occurring-activation pathways. Ca_V3.2 is an example of a voltage-gated Ca²⁺ channel that is activated by membrane depolarization (Panner and Wurster, 2006); ORAI1 is an example of a store-operated Ca²⁺ channel that is activated upon depletion of endoplasmic reticulum Ca²⁺ stores (Lewis, 2011); P2X5 is an example of a purine receptor that facilitates the flow of Ca²⁺ across the plasma membrane in response to extracellular ATP (Surprenant and North, 2009); examples of TRP channels include the canonical mechanosensitive cation channel TRPC1, which can be activated by membrane stretch (Maroto et al., 2005), the vanilloid TRPV1 channels activated by high temperatures (Benham et al., 2003), the melastatin TRPM8 channel activated by lower temperatures (Prevarskaya et al., 2007), the sole member of ankyrin TRPA family TRPA1, which is a key chemoreceptor responsive to reactive chemicals (Moran et al., 2011), TRPM7, which can be directly activated by mechanical stress (Numata et al., 2007), and TRPV6, which has constitutive activity at low [Ca²⁺]_i and physiological membrane potential (Van de Graaf et al., 2006).