Mechanistic basis for targeting sodium channels in breast cancer therapy

The expression of various ion channels is altered in breast cancer cells and increasing evidence suggests that they may be novel prognostic and therapeutic targets. One example is the voltage-gated Na+ channel (VGSC), which is classically responsible for action potentials in electrically excitable cells, including neurons and muscle cells. Interestingly, VGSCs are also expressed in metastatic breast cancer cells, where they regulate Na+ current, membrane potential, cellular migration, invasion and metastasis, suggesting that they may be useful therapeutic targets.

Emerging evidence suggests that VGSCs may promote invasive behaviour via multiple pathways, including adhesion-dependent signalling, Na+-dependent ERK phosphorylation and cytoskeletal reorganisation. However, the exact mechanism(s) by which VGSCs regulate tumour development and metastasis are not well understood.

The aim of this project is to test the hypothesis that VGSCs regulate tumour progression by Na+ conducting and non-conducting mechanisms. We will use targeted approaches to silence or switch on the expression of ion channels, including VGSCs, in order to alter the membrane potential. We will then study the effect of these ion channel alterations on cellular behaviour, including electrophysiological properties, invasion and downstream signalling. We will use a range of sophisticated electrophysiological and microscopy approaches, e.g. whole-cell patch clamp recording, immunohistochemistry, ion- and membrane potential-sensitive dyes together with confocal microscopy, to explore the dependence of cancer cell behaviour on ion channel-induced changes in membrane potential. Using these data, we will also study the potential value of combining VGSC inhibition with conventional therapeutic approaches to inhibit breast cancer cell invasion and metastasis in mice.

The project will therefore expose the student to a range of cutting-edge genetic, in vivo and cell biology techniques. As VGSCs play key roles in a number of diseases, including cancer, this project is expected to provide novel mechanistic insights into the biology of important therapeutic targets.