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I would like to acknowledge Dr. Wan Ezumi Mohd Fuad for her contribution in this article

Introduction to Nav1.5 and neonatal Nav1.5 (nNav1.5)

nNav1.5 is the alternative splice variant of Nav1.5. Nav1.5, an integral membrane protein, is one of the nine members of the voltage-gated sodium channel, alpha subunit (VGSCα) family. Nav1.5 channel typically carries an inward sodium ion current, which determines the sodium ion influx that functions to depolarise the membrane potential during the upstroke of the cardiac action potential. 

Electrophysiological changes in nNav1.5

The electrophysiological changes contributed by alternative splicing at Segment 3 (S3) and S4 of Domain (D1) of Nav1.5 protein, including the extracellular S3–4 linker, grant the prolonged influx of sodium ions (Na+) for the neonatal isoform. The influx of Na+ leads to the efflux of hydrogen ions (H+). The accumulation of H+ ions causes the change in pH of the extracellular environment (perimembranous acidification) causing the activation of cathepsins that eventually contributes to the degradation of the extracellular membrane and eventually promotes the invasion. Such a scenario highlights the association between Nav1.5 (nNav1.5) and Na+/H+ exchanger type 1 (NHE-1), which was reported by Brisson and colleagues.

The role of nNav1.5 in breast cancer metastasis      

Most of the in vitro studies indicated that aggressive breast carcinoma cell lines such as MDA-MB-231 are found to possess a higher expression of Nav1.5 and nNav1.5 as compared to weakly aggressive cell lines such as MCF-7. The presence of nNav1.5 in these aggressive cell lines is associated with various metastatic traits such as migration and invasion. In 2003, a study by Roger et al. revealed the presence of a fast-inward sodium current in a highly metastatic human breast cancer cell line known as MDA-MB-231. The finding was among the earliest studies that linked sodium channels with breast cancer metastasis.  

In 2005, the in vivo expression of nNav1.5 in human breast cancer biopsy samples was discovered whereby it was postulated that the expression of nNav1.5 (sequenced from Nav1.5 positive samples) was related to the presence of lymph node metastasis. In the following year, the role of nNav1.5 in promoting the migration of MDA-MB-231 cells was demonstrated whereby the introduction of docosahexaenoic acid (omega-3) reduced migration of the cells via the downregulation of nNav1.5 expression.

In a breakthrough discovery in 2007, Brackenbury and colleagues reported the suppression of nNav1.5 through RNA interference and NESO-pAb indicated that the protein is responsible for potentiating the invasive behavior of MDA-MB-231. NESOpAb is a polyclonal antibody that recognizes the sequence-specific to nNav1.5 but not the adult isoform, Nav1.5. 

In 2017, a study reported the association between nNav1.5 and the absence of estrogen receptor (ERα). In all ERα-negative tissue, nNav1.5 protein was expressed only in the plasma membrane but in ERα-positive tissues, nNav1.5 protein expression was distributed in both plasma membrane and cytoplasm, which further supports the notion that the neonatal isoform could act as a potential marker for metastatic breast cancer. The study also added that nNav1.5 was absent in all the normal adult tissues except in the breast. Surprisingly, some normal adult breast ductal epithelial cells portrayed vague nNav1.5 immunoreactivity. 

The simplicity of an in vitro assay has opened the path for various pharmacological tests as well. Caffeic acid phenyl ester was introduced as a potential VGSC blocker that reduced invasion in MDA-MB-231 cells. Phenytoin has also been reported to potentially downregulate the expression of Nav1.5 and nNav1.5 in highly metastatic breast cancer cells. 

Immunogenicity of nNav1.5 in regards to breast cancer

In 2020, the immunogenicity of nNav1.5 was tested using serum samples from breast cancer patients. This was the only study that focused on the immunogenicity of nNav1.5 and the detection of antibodies produced naturally against nNav1.5. It was reported that breast cancer patients who never experienced any form of treatment exhibited the highest expression of antibodies against nNav1.5 compared to breast cancer patients with ongoing treatment and healthy participants. The difference in the expression of these antibodies among different treatment groups of breast cancer could be exploited, to be utilized as a potential immunosurveillance marker to reflect the treatment efficiency. 

In a nutshell….

The investigations on the role of nNav1.5 in potentiating breast cancer have been seen to evolve over the years, from the detection in cell lines, followed by clinical samples, and currently, the focus has shifted to promote the immunogenicity of the neonatal isoform.

Reference (A2-May-2021)

Author Biography: The author is currently pursuing fast-track Ph.D in Universiti Sains Malaysia (USM), Malaysia. The author completed her bachelors in Biomedicine (health sciences) and received the King`s Scholarship ‘Biasiswa Yang Di Pertuan Agong’ from the Malaysian government to support her studies (Ph.D). The current field of study pursued is breast cancer immunology focusing on neonatal Nav1.5 (nNav1.5) in regards to breast cancer.

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