Investigating the effect of HIFs and hypoxia on VGSCs in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC): Lacks hormone receptors, more aggressive and challenging to treat compared to ER+ breast cancer.

• Voltage-gated Na+ channels (VGSCs): α subunit and auxiliary β subunits2

o Nav1.5 (SCN5A): Up-regulated in TNBC, promotes invasion and metastasis3.

o β1 (SCN1B): Controls expression and activity of Nav1.5, cell adhesion molecules4.

• Hypoxia: Low O2 in tissues, usually developed in breast tumours

o Hypoxia increases the persistent current of Nav1.5 in the ischaemic heart via SUMOylation and causes an increase in intracellular [Na+] in breast cancer6,7. Hypothesis: HIF-1α is responsible for the upregulation of Nav1.5 in hypoxia, and hypoxia can alter Nav1.5 function post-transcriptionally. These lead to higher channel activity and increased invasive properties of breast cancer.

• Hypoxia-inducible factors (HIFs): Key regulators of the cellular hypoxic response

o HIF-1α is the most critical subunit, overexpressed in breast cancer and significantly enhances metastasis.